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Journal articles on the topic 'FKBPs'

Author: Grafiati
Published: 10 January 2023
Last updated: 28 January 2023

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1

Wang, Chin-Chou, Wan-Jou Shen, Gangga Anuraga, Yu-Hsiu Hsieh, Hoang Dang Khoa Ta, Do Thi Minh Xuan, Chiu-Fan Shen, Chih-Yang Wang, and Wei-Jan Wang. "Penetrating Exploration of Prognostic Correlations of the FKBP Gene Family with Lung Adenocarcinoma." Journal of Personalized Medicine 13, no. 1 (December 26, 2022): 49. http://dx.doi.org/10.3390/jpm13010049.

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The complexity of lung adenocarcinoma (LUAD), the development of which involves many interacting biological processes, makes it difficult to find therapeutic biomarkers for treatment. FK506-binding proteins (FKBPs) are composed of 12 members classified as conservative intracellular immunophilin family proteins, which are often connected to cyclophilin structures by tetratricopeptide repeat domains and have peptidyl prolyl isomerase activity that catalyzes proline from residues and turns the trans form into the cis form. Since FKBPs belong to chaperone molecules and promote protein folding, previous studies demonstrated that FKBP family members significantly contribute to the degradation of damaged, misfolded, abnormal, and foreign proteins. However, transcript expressions of this gene family in LUAD still need to be more fully investigated. In this research, we adopted high-throughput bioinformatics technology to analyze FKBP family genes in LUAD to provide credible information to clinicians and promote the development of novel cancer target drugs in the future. The current data revealed that the messenger (m)RNA levels of FKBP2, FKBP3, FKBP4, FKBP10, FKBP11, and FKBP14 were overexpressed in LUAD, and FKBP10 had connections to poor prognoses among LUAD patients in an overall survival (OS) analysis. Based on the above results, we selected FKBP10 to further conduct a comprehensive analysis of the downstream pathway and network. Through a DAVID analysis, we found that FKBP10 was involved in mitochondrial electron transport, NADH to ubiquinone transport, mitochondrial respiratory chain complex I assembly, etc. The MetaCore pathway analysis also indicated that FKBP10 was involved in "Ubiquinone metabolism", "Translation_(L)-selenoaminoacid incorporation in proteins during translation", and "Transcription_Negative regulation of HIF1A function". Collectively, this study revealed that FKBP family members are both significant prognostic biomarkers for lung cancer progression and promising clinical therapeutic targets, thus providing new targets for treating LUAD patients.
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2

Galat, Andrzej. "Compression of Large Sets of Sequence Data Reveals Fine Diversification of Functional Profiles in Multigene Families of Proteins: A Study for Peptidyl-Prolyl cis/trans Isomerases (PPIase)." Biomolecules 9, no. 2 (February 11, 2019): 59. http://dx.doi.org/10.3390/biom9020059.

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In this technical note, we describe analyses of more than 15,000 sequences of FK506-binding proteins (FKBP) and cyclophilins, also known as peptidyl-prolyl cis/trans isomerases (PPIases). We have developed a novel way of displaying relative changes of amino acid (AA)-residues at a given sequence position by using heat-maps. This type of representation allows simultaneous estimation of conservation level in a given sequence position in the entire group of functionally-related paralogues (multigene family of proteins). We have also proposed that at least two FKBPs, namely FKBP36, encoded by the Fkbp6 gene and FKBP51, encoded by the Fkbp5 gene, can form dimers bound via a disulfide bridge in the nucleus. This type of dimer may have some crucial function in the regulation of some nuclear complexes at different stages of the cell cycle.
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3

Bultynck, Geert, Daniela Rossi, Geert Callewaert, Ludwig Missiaen, Vincenzo Sorrentino, Jan B. Parys, and Humbert De Smedt. "The Conserved Sites for the FK506-binding Proteins in Ryanodine Receptors and Inositol 1,4,5-Trisphosphate Receptors Are Structurally and Functionally Different." Journal of Biological Chemistry 276, no. 50 (October 11, 2001): 47715–24. http://dx.doi.org/10.1074/jbc.m106573200.

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We compared the interaction of the FK506-binding protein (FKBP) with the type 3 ryanodine receptor (RyR3) and with the type 1 and type 3 inositol 1,4,5-trisphosphate receptor (IP3R1 and IP3R3), using a quantitative GST-FKBP12 and GST-FKBP12.6 affinity assay. We first characterized and mapped the interaction of the FKBPs with the RyR3. GST-FKBP12 as well as GST-FKBP12.6 were able to bind ∼30% of the solubilized RyR3. The interaction was completely abolished by FK506, strengthened by the addition of Mg2+, and weakened in the absence of Ca2+but was not affected by the addition of cyclic ADP-ribose. By using proteolytic mapping and site-directed mutagenesis, we pinpointed Val2322, located in the central modulatory domain of the RyR3, as a critical residue for the interaction of RyR3 with FKBPs. Substitution of Val2322for leucine (as in IP3R1) or isoleucine (as in RyR2) decreased the binding efficiency and shifted the selectivity to FKBP12.6; substitution of Val2322for aspartate completely abolished the FKBP interaction. Importantly, the occurrence of the valylprolyl residue as α-helix breaker was an important determinant of FKBP binding. This secondary structure is conserved among the different RyR isoforms but not in the IP3R isoforms. A chimeric RyR3/IP3R1, containing the core of the FKBP12-binding site of IP3R1 in the RyR3 context, retained this secondary structure and was able to interact with FKBPs. In contrast, IP3Rs did not interact with the FKBP isoforms. This indicates that the primary sequence in combination with the local structural environment plays an important role in targeting the FKBPs to the intracellular Ca2+-release channels. Structural differences in the FKBP-binding site of RyRs and IP3Rs may contribute to the occurrence of a stable interaction between RyR isoforms and FKBPs and to the absence of such interaction with IP3Rs.
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4

McKeen, Hayley D., Donal J. Brennan, Shauna Hegarty, Fiona Lanigan, Karin Jirstrom, Christopher Byrne, Anita Yakkundi, Helen O. McCarthy, William M. Gallagher, and Tracy Robson. "The emerging role of FK506-binding proteins as cancer biomarkers: a focus on FKBPL." Biochemical Society Transactions 39, no. 2 (March 22, 2011): 663–68. http://dx.doi.org/10.1042/bst0390663.

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FKBPs (FK506-binding proteins) have long been recognized as key regulators of the response to immunosuppressant drugs and as co-chaperones of steroid receptor complexes. More recently, evidence has emerged suggesting that this diverse protein family may also represent cancer biomarkers owing to their roles in cancer progression and response to treatment. FKBPL (FKBP-like) is a novel FKBP with roles in GR (glucocorticoid receptor), AR (androgen receptor) and ER (oestrogen receptor) signalling. FKBPL binds Hsp90 (heat-shock protein 90) and modulates translocation, transcriptional activation and phosphorylation of these steroid receptors. It has been proposed as a novel prognostic and predictive biomarker, where high levels predict for increased recurrence-free survival in breast cancer patients and enhanced sensitivity to endocrine therapy. Since this protein family has roles in a plethora of signalling pathways, its members represent novel prognostic markers and therapeutic targets for cancer diagnosis and treatment.
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5

MO, Yin-yuan, J. SESHU, Dong WANG, and Louis P. MALLAVIA. "Synthesis in Escherichia coli of two smaller enzymically active analogues of Coxiella burnetii macrophage infectivity potentiator (CbMip) protein utilizing a single open reading frame from the cbmip gene." Biochemical Journal 335, no. 1 (October 1, 1998): 67–77. http://dx.doi.org/10.1042/bj3350067.

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FK506-binding proteins (FKBPs) have been identified in a variety of eukaryotic and prokaryotic organisms. Macrophage infectivity potentiator (CbMip, 23.5 kDa) protein of the obligate intracellular bacterium, Coxiella burnetii, was shown previously to belong to the family of FKBPs based on sequence homology and peptidyl-prolyl cis/trans isomerase (PPIase) activity. Further characterization of the cbmip gene has identified two additional proteins with molecular masses of 15.5 and 15.0 kDa that are synthesized, in addition to the 23.5 kDa CbMip, when expressed in Escherichia coli. Amino acid sequencing at the N-terminus combined with transcription and translation fusion expression revealed that the two proteins were synthesized from the same open reading frame of the cbmip gene, but starting at different internal translation start codons, probably by translational reinitiation. When the internal methionines serving as start sites were replaced with lysine by site-directed mutagenesis, the synthesis of 15.5 and 15.0 kDa proteins was abolished even though the synthesis of 23.5 kDa CbMip was intact. This confirmed that the 15.5 and 15.0 kDa proteins are indeed generated by translational reinitiation and are not degradation products of the 23.5 kDa protein. Like other FKBPs, both 15.5 and 15.0 kDa proteins exhibit PPIase activity. Because they share significant sequence homology with FKBPs and have a similar PPIase activity, 15.5 and 15.0 kDa proteins are designated as C. burnetiiFKBP (Cb-FKBP) analogues I and II, respectively. TnphoA mutagenesis demonstrated that whereas the large protein (CbMip) is secreted, Cb-FKBP analogues I and II are cytoplasmic, indicating that structural variations could allow for different subcellular compartmentalization of similar proteins. Western-blot analysis of lysates of purified C. burnetii using a CbMip-specific monoclonal antibody revealed the presence of a protein migrating at ≈ 15 kDa, indicating the presence of smaller Cb-FKBP analogue(s) in C. burnetii, although at much lower levels compared with 23.5 kDa CbMip. This unique gene organization seen with cbmip may provide the organism with a mechanism of efficient use of its limited genetic information to synthesize proteins that are structurally different yet functionally similar.
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6

Geisler, Markus. "Regulation von ABC-Transportern durch FKBPs." BIOspektrum 27, no. 2 (March 2021): 131–34. http://dx.doi.org/10.1007/s12268-021-1548-x.

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AbstractThe plant hormone auxin is distributed in the plant by a sophisticated network of importers and exporters, including members of the ABCB subclass of ATP-binding cassette (ABC) transporters. ABCB-mediated auxin transport is controlled by Twisted Dwarf1, a member of the FK506-binding protein (FKBP) family. Here, we summarize current knowledge on ABC transporter regulation by FKBPs, which seems to be conserved over kingdoms and ABC subfamilies arguing for conserved mechanism of plant and mammalian post-translational transporter regulation.
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7

Yadav, Ravi P., Lokesh Gakhar, Liping Yu, and Nikolai O. Artemyev. "Unique structural features of the AIPL1–FKBP domain that support prenyl lipid binding and underlie protein malfunction in blindness." Proceedings of the National Academy of Sciences 114, no. 32 (July 24, 2017): E6536—E6545. http://dx.doi.org/10.1073/pnas.1704782114.

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FKBP-domain proteins (FKBPs) are pivotal modulators of cellular signaling, protein folding, and gene transcription. Aryl hydrocarbon receptor-interacting protein-like 1 (AIPL1) is a distinctive member of the FKBP superfamily in terms of its biochemical properties, and it plays an important biological role as a chaperone of phosphodiesterase 6 (PDE6), an effector enzyme of the visual transduction cascade. Malfunction of mutant AIPL1 proteins triggers a severe form of Leber congenital amaurosis and leads to blindness. The mechanism underlying the chaperone activity of AIPL1 is largely unknown, but involves the binding of isoprenyl groups on PDE6 to the FKBP domain of AIPL1. We solved the crystal structures of the AIPL1–FKBP domain and its pathogenic mutant V71F, both in the apo form and in complex with isoprenyl moieties. These structures reveal a module for lipid binding that is unparalleled within the FKBP superfamily. The prenyl binding is enabled by a unique “loop-out” conformation of the β4-α1 loop and a conformational “flip-out” switch of the key W72 residue. A second major conformation of apo AIPL1–FKBP was identified by NMR studies. This conformation, wherein W72 flips into the ligand-binding pocket and renders the protein incapable of prenyl binding, is supported by molecular dynamics simulations and appears to underlie the pathogenicity of the V71F mutant. Our findings offer critical insights into the mechanisms that underlie AIPL1 function in health and disease, and highlight the structural and functional diversity of the FKBPs.
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8

Chambraud, Béatrice, Cillian Byrne, Geri Meduri, Etienne Emile Baulieu, and Julien Giustiniani. "FKBP52 in Neuronal Signaling and Neurodegenerative Diseases: A Microtubule Story." International Journal of Molecular Sciences 23, no. 3 (February 3, 2022): 1738. http://dx.doi.org/10.3390/ijms23031738.

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The FK506-binding protein 52 (FKBP52) belongs to a large family of ubiquitously expressed and highly conserved proteins (FKBPs) that share an FKBP domain and possess Peptidyl-Prolyl Isomerase (PPIase) activity. PPIase activity catalyzes the isomerization of Peptidyl-Prolyl bonds and therefore influences target protein folding and function. FKBP52 is particularly abundant in the nervous system and is partially associated with the microtubule network in different cell types suggesting its implication in microtubule function. Various studies have focused on FKBP52, highlighting its importance in several neuronal microtubule-dependent signaling pathways and its possible implication in neurodegenerative diseases such as tauopathies (i.e., Alzheimer disease) and alpha-synucleinopathies (i.e., Parkinson disease). This review summarizes our current understanding of FKBP52 actions in the microtubule environment, its implication in neuronal signaling and function, its interactions with other members of the FKBPs family and its involvement in neurodegenerative disease.
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9

Liu, Fei, Xiao-Long Wei, Hao Li, Ji-Fu Wei, Yong-Qing Wang, and Xiao-Jian Gong. "Molecular Evolution of the Vertebrate FK506 Binding Protein 25." International Journal of Genomics 2014 (2014): 1–9. http://dx.doi.org/10.1155/2014/402603.

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FK506 binding proteins (FKBPs) belong to immunophilins with peptidyl-prolyl isomerases (PPIases) activity. FKBP25 (also known as FKBP3) is one of the nuclear DNA-binding proteins in the FKBPs family, which plays an important role in regulating transcription and chromatin structure. The calculation of nonsynonymous and synonymous substitution rates suggested that FKBP25 undergoes purifying selection throughout the whole vertebrate evolution. Moreover, the result of site-specific tests showed that no sites were detected under positive selection. Only one PPIase domain was detected by searching FKBP25 sequences at Pfam and SMART domain databases. Mammalian FKBP25 possess exon-intron conservation, although conservation in the whole vertebrate lineage is incomplete. The result of this study suggests that the purifying selection triggers FKBP25 evolutionary history, which allows us to discover the complete role of the PPIase domain in the interaction between FKBP25 and nuclear proteins. Moreover, intron alterations during FKBP25 evolution that regulate gene splicing may be involved in the purifying selection.
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10

Pagani, Alessia, Mariateresa Pettinato, Alessandro Dulja, Silvia Colucci, Mariam Aghajan, Valeria Furiosi, Martina U. Muckenthaler, Shuling Guo, Antonella Nai, and Laura Silvestri. "Dissecting the Mechanisms of Hepcidin and BMP-SMAD Pathway Regulation By FKBP12." Blood 138, Supplement 1 (November 5, 2021): 2008. http://dx.doi.org/10.1182/blood-2021-152172.

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Abstract The BMP-SMAD pathway is activated when a dimeric ligand (BMP) interacts with a dimeric serine threonine kinase receptor (BMPRII) and triggers the activation of a dimeric BMP type I receptor (BMPRI). Catalytically active BMPRIs phosphorylate SMAD1/5/8 that, upon SMAD4 binding, translocate to the nucleus to regulate the expression of BMP target genes, including hepcidin. Hepcidin is the main regulator of iron homeostasis that controls body iron levels by binding and blocking the sole iron exporter ferroportin. In agreement, hepcidin expression is homeostatically activated by serum and liver iron, and its deficiency is a common hallmark of Hereditary Hemochromatosis (HH) and the major cause of iron overload in beta thalassemia. The components of the BMP-SMAD pathway relevant for hepcidin regulation are ALK2 and ALK3 (BMPRI); BMPR2 and ACVR2A (BMPRII), BMP2 and BMP6 (BMP ligands). Recently, we have identified the immunophilin FKBP12 as an inhibitor of hepcidin and demonstrated that FKBP12 binds ALK2 to avoid ligand-independent activation of the BMP-SMAD pathway. To investigate the mechanism of BMP-SMAD pathway and hepcidin regulation by FKBP12, we performed in vitro, ex vivo and in vivo studies. We found that FKBP12 sequestration by the immunosuppressive drug Tacrolimus (TAC) stabilizes ALK2-ALK2 homodimers and ALK2-ALK3 heterodimers in a transfected human hepatoma cell line. In addition, it increases the interaction of ALK2 with ACVR2A and BMPR2. To investigate the role of FKBP12 on BMP-SMAD signaling, BMPRI and II were silenced in murine primary hepatocytes. Despite FKBP12 co-immunoprecipitates only with ALK2, silencing of Alk2 and Alk3 completely blunts TAC-mediated BMP-SMAD pathway activation, suggesting that FKBP12 functionally interacts also with ALK3. Acvr2a silencing impairs TAC-dependent hepcidin upregulation, whereas Bmpr2 silencing does not. As expected, Fkbp12 silencing abrogates hepcidin upregulation by TAC, confirming the main role of this immunophilin in hepcidin regulation. In vivo, TAC treatment upregulates hepcidin in wild type and HH mouse models, but surprisingly, Fkbp12 mRNA downregulation by ASOs does not. Interestingly, Fkbp 2, 4 and 8 are highly expressed in murine hepatocytes and, according to literature data, are able to bind to TAC. Of note, Fkbp12 is the least expressed immunophilin in murine primary hepatocytes. To further investigate the FKBPs involved in TAC-dependent hepcidin regulation, Fkbp2, 4 and 8 were knockdown in murine primary HCs that were then treated with TAC. The TAC effect is preserved in siFkbp2- and siFkbp4-derived HCs, but abolished when Fkbp8 was downregulated. Overall these data suggest that: 1) FKBP12 regulates BMP-SMAD signaling by favoring ALK2-ALK3 homo and heterodimerization, and interaction with BMPRII in the absence of ligands; 2) TAC-mediated hepcidin upregulation is dependent upon ALK2, ALK3, ACVR2A, FKBP12 and FKBP8. 3) In vivo, TAC treatment upregulates hepcidin whereas Fkbp12 silencing does not, suggesting the existence of redundancy between the different FKBPs. Further studies are needed to dissect the role of FKBP8 in BMP-SMAD pathway and hepcidin regulation. Disclosures Aghajan: Ionis Pharmaceuticals, Inc.: Current Employment. Muckenthaler: Silence Therapeutics: Research Funding. Guo: Ionis Pharmaceuticals, Inc.: Current Employment.
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11

Alag, Reema, Asha Manikkoth Balakrishna, Sreekanth Rajan, Insaf A. Qureshi, Joon Shin, Julien Lescar, Gerhard Grüber, and Ho Sup Yoon. "Structural Insights into Substrate Binding by Pv FKBP35, a Peptidylprolyl cis-trans Isomerase from the Human Malarial Parasite Plasmodium vivax." Eukaryotic Cell 12, no. 4 (February 22, 2013): 627–34. http://dx.doi.org/10.1128/ec.00016-13.

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ABSTRACT The immunosuppressive drug FK506 binding proteins (FKBPs), an immunophilin family with the immunosuppressive drug FK506 binding property, exhibit peptidylprolyl cis-trans isomerase (PPIase) activity. While the cyclophilin-catalyzed peptidylprolyl isomerization of X-Pro peptide bonds has been extensively studied, the mechanism of the FKBP-mediated peptidylprolyl isomerization remains uncharacterized. Thus, to investigate the binding of FKBP with its substrate and the underlying catalytic mechanism of the FKBP-mediated proline isomerization, here we employed the FK506 binding domain (FKBD) of the human malarial parasite Plasmodium vivax FK506 binding protein 35 ( Pv FKBP35) and examined the details of the molecular interaction between the isomerase and a peptide substrate. The crystallographic structures of apo Pv FKBD35 and its complex with the tetrapeptide substrate succinyl-Ala-Leu-Pro-Phe- p -nitroanilide (sALPFp) determined at 1.4 Å and 1.65 Å resolutions, respectively, showed that the substrate binds to Pv FKBD35 in a cis conformation. Nuclear magnetic resonance (NMR) studies demonstrated the chemical shift perturbations of D55, H67, V73, and I74 residues upon the substrate binding. In addition, the X-ray crystal structure, along with the mutational studies, shows that Y100 is a key residue for the catalytic activity. Taken together, our results provide insights into the catalytic mechanism of Pv FKBP35-mediated cis-trans isomerization of substrate and ultimately might aid designing substrate mimetic inhibitors targeting the malarial parasite FKBPs.
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Baughman, G., G. J. Wiederrecht, N. F. Campbell, M. M. Martin, and S. Bourgeois. "FKBP51, a novel T-cell-specific immunophilin capable of calcineurin inhibition." Molecular and Cellular Biology 15, no. 8 (August 1995): 4395–402. http://dx.doi.org/10.1128/mcb.15.8.4395.

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The immunosuppressive drugs FK506 and cyclosporin A block T-lymphocyte proliferation by inhibiting calcineurin, a critical signaling molecule for activation. Multiple intracellular receptors (immunophilins) for these drugs that specifically bind either FK506 and rapamycin (FK506-binding proteins [FKBPs]) or cyclosporin A (cyclophilins) have been identified. We report the cloning and characterization of a new 51-kDa member of the FKBP family from murine T cells. The novel immunophilin, FKBP51, is distinct from the previously isolated and sequenced 52-kDa murine FKBP, demonstrating 53% identity overall. Importantly, Western blot (immunoblot) analysis showed that unlike all other FKBPs characterized to date, FKBP51 expression was largely restricted to T cells. Drug binding to recombinant FKBP51 was demonstrated by inhibition of peptidyl prolyl isomerase activity. As judged from peptidyl prolyl isomerase activity, FKBP51 had a slightly higher affinity for rapamycin than for FK520, an FK506 analog. FKBP51, when complexed with FK520, was capable of inhibiting calcineurin phosphatase activity in an in vitro assay system. Inhibition of calcineurin phosphatase activity has been implicated both in the mechanism of immunosuppression and in the observed toxic side effects of FK506 in nonlymphoid cells. Identification of a new FKBP that can mediate calcineurin inhibition and is restricted in its expression to T cells suggests that new immunosuppressive drugs may be identified that, by virtue of their specific interaction with FKBP51, would be targeted in their site of action.
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13

Norville, Isobel H., Katrin Breitbach, Kristin Eske-Pogodda, Nicholas J. Harmer, Mitali Sarkar-Tyson, Richard W. Titball, and Ivo Steinmetz. "A novel FK-506-binding-like protein that lacks peptidyl-prolyl isomerase activity is involved in intracellular infection and in vivo virulence of Burkholderia pseudomallei." Microbiology 157, no. 9 (September 1, 2011): 2629–38. http://dx.doi.org/10.1099/mic.0.049163-0.

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Burkholderia pseudomallei is a facultative intracellular bacterial pathogen causing melioidosis, an often fatal infectious disease that is endemic in several tropical and subtropical areas around the world. We previously described a Ptk2 cell-based plaque assay screening system of B. pseudomallei transposon mutants that led to the identification of several novel virulence determinants. Using this approach we identified a mutant with reduced plaque formation in which the BPSL0918 gene was disrupted. BPSL0918 encodes a putative FK-506-binding protein (FKBP) representing a family of proteins that typically possess peptidyl-prolyl isomerase (PPIase) activity. A B. pseudomallei ΔBPSL0918 mutant showed a severely impaired ability to resist intracellular killing and to replicate within primary macrophages. Complementation of the mutant fully restored its ability to grow intracellularly. Moreover, B. pseudomallei ΔBPSL0918 was significantly attenuated in a murine model of infection. Structural modelling confirmed a modified FKBP fold of the BPSL0918-encoded protein but unlike virulence-associated FKBPs from other pathogenic bacteria, recombinant BPSL0918 protein did not possess PPIase activity in vitro. In accordance with this observation BPSL0918 exhibits several mutations in residues that have been proposed to mediate PPIase activity in other FKBPs. To our knowledge this B. pseudomallei FKBP represents the first example of this protein family which lacks PPIase activity but is important in intracellular infection of a bacterial pathogen.
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Dilworth, David, Fade Gong, Kyle Miller, and Christopher J. Nelson. "FKBP25 participates in DNA double-strand break repair." Biochemistry and Cell Biology 98, no. 1 (February 2020): 42–49. http://dx.doi.org/10.1139/bcb-2018-0328.

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FK506-binding proteins (FKBPs) alter the conformation of proteins via cis–trans isomerization of prolyl-peptide bonds. While this activity can be demonstrated in vitro, the intractability of detecting prolyl isomerization events in cells has limited our understanding of the biological processes regulated by FKBPs. Here we report that FKBP25 is an active participant in the repair of DNA double-strand breaks (DSBs). FKBP25 influences DSB repair pathway choice by promoting homologous recombination (HR) and suppressing single-strand annealing (SSA). Consistent with this observation, cells depleted of FKBP25 form fewer Rad51 repair foci in response to etoposide and ionizing radiation, and they are reliant on the SSA repair factor Rad52 for viability. We find that FKBP25’s catalytic activity is required for promoting DNA repair, which is the first description of a biological function for this enzyme activity. Consistent with the importance of the FKBP catalytic site in HR, rapamycin treatment also impairs homologous recombination, and this effect is at least in part independent of mTor. Taken together these results identify FKBP25 as a component of the DNA DSB repair pathway.
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15

Dreno, Luce, Carolina Tiraboschi, Sofian Lacoste, Sofia Calpe Gomez, Marine F. Garrido, Matthieu Bertrand, Mariana Tannoury, et al. "Abstract 400: Functional, structural and binding studies of the atypical ER-resident protein FKBP7, a potential target in chemoresistant prostate cancer." Cancer Research 82, no. 12_Supplement (June 15, 2022): 400. http://dx.doi.org/10.1158/1538-7445.am2022-400.

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Abstract Background: Metastatic Castration Resistant Prostate Cancer (mCRPC) is the latest stage of Prostate Cancer (PCa). Despite the use of taxane-based chemotherapies Docetaxel and Cabazitaxel, mCRPC remains lethal due to chemoresistance. We recently identified FKBP7 as a potential therapeutic target of interest in PCa. FKBP7 is overexpressed in taxane-resistant PCa cells and impacts both cell proliferation and Docetaxel efficacy in chemoresistant models. We demonstrated FKBP7 affects translation and binds to the translation initiation complex eIF4F. FKBP7 is an ER-resident FKBP, but its properties remain poorly described. Methods: FKBP7 expression upon chemotherapy treatment was assessed by Western Blot and correlation between FKBP7 expression and clinical prognosis was examined on public cancer databases. Subcellular localization of FKBP7 was addressed by digitonin-based fractionation. Finally, FKBP7-predicted structure was obtained with structural modeling servers and sequence alignments were performed on AliView. We then produced and purified the recombinant catalytic domain of FKBP7 and collected high quality 15N HSQC NMR spectra. Afterwards, we examined its interaction with well-known FKBP ligands. Results: Increased FKBP7 expression was observed upon treatment with several cytotoxic chemotherapies in PCa-cell lines, and TCGA data underlined FKBP7 impacts survival in other cancers than PCa. Together, this suggests an enlarged potential involvement of FKBP7 in adaptive resistance. Mechanistically, in taxane-resistant models, FKBP7 overexpression did not result from higher protein stability but rather from a transcriptional regulation. Preliminary results of subcellular fractionation showed FKBP7 is present in the Endoplasmic Reticulum (ER) and seems to localize in the cytosol, independently of proteasomal degradation. We also confirmed FKBP7 is N45-glycosylated and observed that cytosolic-FKBP7 appears mainly glycosylated. This suggests that the ER-resident FKBP7 could be refluxed in the cytosol depending on its glycosylation state to regulate the activity of the cytosolic eIF4F complex. We are currently validating this hypothesis. At last, structural modeling predicted a FKBP-type fold with a potential FKBP7 substrate specificity as its catalytic pocket presents distinct composition for charge and bulkiness compared to other FKBPs. Accordingly, FKBP7 strongly binds Rapamycin and Everolimus, but surprisingly not FK506, confirming a selective binding profile. Conclusion: Our work depicts the recently identified FKBP7/eIF4F pathway in PCa-resistance and points atypical properties for the ER-resident FKBP7. It also indicates FKBP7 could be a druggable target in adaptive resistance of other solid cancers. Besides, we gathered original data on its structure and specificity for future drug-targeting strategies. Citation Format: Luce Dreno, Carolina Tiraboschi, Sofian Lacoste, Sofia Calpe Gomez, Marine F. Garrido, Matthieu Bertrand, Mariana Tannoury, Eric Jacquet, Naima Nhiri, Yohann Loriot, Karim Fizazi, Daniel Compagno, Nadine Assrir, Ewen Lescop, Anne Chauchereau. Functional, structural and binding studies of the atypical ER-resident protein FKBP7, a potential target in chemoresistant prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 400.
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Ünal, Can M., and Michael Steinert. "FKBPs in bacterial infections." Biochimica et Biophysica Acta (BBA) - General Subjects 1850, no. 10 (October 2015): 2096–102. http://dx.doi.org/10.1016/j.bbagen.2014.12.018.

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17

Han, Ruifang, Ying Wang, Chen Chen, Zhuo Zhao, and Huaifeng Mi. "De-Novo Cloning of FKBP23 cDNA from Pig ER Using Nested PCR." Zeitschrift für Naturforschung C 64, no. 3-4 (April 1, 2009): 297–302. http://dx.doi.org/10.1515/znc-2009-3-423.

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FK506 binding proteins (FKBPs) in cells are known as immunophilins. We have identifi ed and characterized a cDNA encoding an endoplasmic reticulum (ER) immunophilin, FKBP23, from pig liver by nested PCR. The predicted amino acid sequence of pig FKBP23 shows high identity to those of human FKBP23 and mouse FKBP23. It possesses a conserved FKBP-type peptidylprolyl cis-trans isomerase (PPIase) domain and EF-hand domain. We constructed a plasmid to express pFKBP23. Furthermore, we proved that the recombinant pFKBP23 can specifi cally bind to natural BiP, the main protein of the molecular chaperone Hsp70 in ER lumen; the binding is interrelated with the Ca2+ concentration just as the FKBP23 from mice.
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Hausch, Felix, Christian Kozany, Marily Theodoropoulou, and Anne-Katrin Fabian. "FKBPs and the Akt/mTOR pathway." Cell Cycle 12, no. 15 (August 2013): 2366–70. http://dx.doi.org/10.4161/cc.25508.

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Yao, Ya-Li, Ya-Chen Liang, Huai-Huei Huang, and Wen-Ming Yang. "FKBPs in chromatin modification and cancer." Current Opinion in Pharmacology 11, no. 4 (August 2011): 301–7. http://dx.doi.org/10.1016/j.coph.2011.03.005.

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20

Heitman, J., A. Koller, J. Kunz, R. Henriquez, A. Schmidt, N. R. Movva, and M. N. Hall. "The immunosuppressant FK506 inhibits amino acid import in Saccharomyces cerevisiae." Molecular and Cellular Biology 13, no. 8 (August 1993): 5010–19. http://dx.doi.org/10.1128/mcb.13.8.5010-5019.1993.

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The immunosuppressants cyclosporin A, FK506, and rapamycin inhibit growth of unicellular eukaryotic microorganisms and also block activation of T lymphocytes from multicellular eukaryotes. In vitro, these compounds bind and inhibit two different types of peptidyl-prolyl cis-trans isomerases. Cyclosporin A binds cyclophilins, whereas FK506 and rapamycin bind FK506-binding proteins (FKBPs). Cyclophilins and FKBPs are ubiquitous, abundant, and targeted to multiple cellular compartments, and they may fold proteins in vivo. Previously, a 12-kDa cytoplasmic FKBP was shown to be only one of at least two FK506-sensitive targets in the yeast Saccharomyces cerevisiae. We find that a second FK506-sensitive target is required for amino acid import. Amino acid-auxotrophic yeast strains (trp1 his4 leu2) are FK506 sensitive, whereas prototrophic strains (TRP1 his4 leu2, trp1 HIS4 leu2, and trp1 his4 LEU2) are FK506 resistant. Amino acids added exogenously to the growth medium mitigate FK506 toxicity. FK506 induces GCN4 expression, which is normally induced by amino acid starvation. FK506 inhibits transport of tryptophan, histidine, and leucine into yeast cells. Lastly, several genes encoding proteins involved in amino acid import or biosynthesis confer FK506 resistance. These findings demonstrate that FK506 inhibits amino acid import in yeast cells, most likely by inhibiting amino acid transporters. Amino acid transporters are integral membrane proteins which import extracellular amino acids and constitute a protein family sharing 30 to 35% identity, including eight invariant prolines. Thus, the second FK506-sensitive target in yeast cells may be a proline isomerase that plays a role in folding amino acid transporters during transit through the secretory pathway.
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Heitman, J., A. Koller, J. Kunz, R. Henriquez, A. Schmidt, N. R. Movva, and M. N. Hall. "The immunosuppressant FK506 inhibits amino acid import in Saccharomyces cerevisiae." Molecular and Cellular Biology 13, no. 8 (August 1993): 5010–19. http://dx.doi.org/10.1128/mcb.13.8.5010.

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The immunosuppressants cyclosporin A, FK506, and rapamycin inhibit growth of unicellular eukaryotic microorganisms and also block activation of T lymphocytes from multicellular eukaryotes. In vitro, these compounds bind and inhibit two different types of peptidyl-prolyl cis-trans isomerases. Cyclosporin A binds cyclophilins, whereas FK506 and rapamycin bind FK506-binding proteins (FKBPs). Cyclophilins and FKBPs are ubiquitous, abundant, and targeted to multiple cellular compartments, and they may fold proteins in vivo. Previously, a 12-kDa cytoplasmic FKBP was shown to be only one of at least two FK506-sensitive targets in the yeast Saccharomyces cerevisiae. We find that a second FK506-sensitive target is required for amino acid import. Amino acid-auxotrophic yeast strains (trp1 his4 leu2) are FK506 sensitive, whereas prototrophic strains (TRP1 his4 leu2, trp1 HIS4 leu2, and trp1 his4 LEU2) are FK506 resistant. Amino acids added exogenously to the growth medium mitigate FK506 toxicity. FK506 induces GCN4 expression, which is normally induced by amino acid starvation. FK506 inhibits transport of tryptophan, histidine, and leucine into yeast cells. Lastly, several genes encoding proteins involved in amino acid import or biosynthesis confer FK506 resistance. These findings demonstrate that FK506 inhibits amino acid import in yeast cells, most likely by inhibiting amino acid transporters. Amino acid transporters are integral membrane proteins which import extracellular amino acids and constitute a protein family sharing 30 to 35% identity, including eight invariant prolines. Thus, the second FK506-sensitive target in yeast cells may be a proline isomerase that plays a role in folding amino acid transporters during transit through the secretory pathway.
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Fabian, Anne-Katrin, Andreas März, Sonja Neimanis, Ricardo M. Biondi, Christian Kozany, and Felix Hausch. "InterAKTions with FKBPs - Mutational and Pharmacological Exploration." PLoS ONE 8, no. 2 (February 28, 2013): e57508. http://dx.doi.org/10.1371/journal.pone.0057508.

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Hausch, Felix. "FKBPs and their role in neuronal signaling." Biochimica et Biophysica Acta (BBA) - General Subjects 1850, no. 10 (October 2015): 2035–40. http://dx.doi.org/10.1016/j.bbagen.2015.01.012.

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MONAGHAN, PAUL, DARREN B. LENEGHAN, WESLEY SHAW, and ANGUS BELL. "The antimalarial action of FK506 and rapamycin: evidence for a direct effect on FK506-binding protein PfFKBP35." Parasitology 144, no. 7 (March 9, 2017): 869–76. http://dx.doi.org/10.1017/s0031182017000245.

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SUMMARYFK506 and rapamycin (Rap) are immunosuppressive drugs that act principally on T-lymphocytes. The receptors for both drugs are FK506-binding proteins (FKBPs), but the molecular mechanisms of immunosuppression differ. An FK506–FKBP complex inhibits the protein phosphatase calcineurin, blocking a key step in T-cell activation, while the Rap –FKBP complex binds to the protein kinase target of rapamycin (TOR), which is involved in a subsequent signalling pathway. Both drugs, and certain non-immunosuppressive compounds related to FK506, have potent antimalarial activity. There is however conflicting evidence on the involvement of Plasmodium calcineurin in the action of FK506, and the parasite lacks an apparent TOR homologue. We therefore set out to establish whether inhibition of the Plasmodium falciparum FKBP PfFKBP35 itself might be responsible for the antimalarial effects of FK506 and Rap. Similarities in the antiparasitic actions of FK506 and Rap would constitute indirect evidence for this hypothesis. FK506 and Rap acted indistinguishably on: (i) specificity for different intra-erythrocytic stages in culture, (ii) kinetics of killing or irreversible growth arrest of parasites and (iii) interactions with other antimalarial agents. Furthermore, PfFKBP35's inhibitory effect on calcineurin was independent of FK506 under a range of conditions, suggesting that calcineurin is unlikely to be involved in the antimalarial action of FK506.
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Ideno, Akira, Masahiro Furutani, Yoshitaka Iba, Yoshikazu Kurosawa, and Tadashi Maruyama. "FK506 Binding Protein from the Hyperthermophilic Archaeon Pyrococcus horikoshii Suppresses the Aggregation of Proteins in Escherichia coli." Applied and Environmental Microbiology 68, no. 2 (February 2002): 464–69. http://dx.doi.org/10.1128/aem.68.2.464-469.2002.

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ABSTRACT The 29-kDa FK506 binding protein (FKBP) gene is the only peptidyl-prolyl cis-trans isomerase (PPIase) gene in the genome of Pyrococcus horikoshii. We characterized the function of this FKBP (PhFKBP29) and used it to increase the production yield of soluble recombinant protein in Escherichia coli. The PPIase activity (k cat/Km ) of PhFKBP29 was found to be much lower than that of other archaeal 16- to 18-kDa FKBPs by a chymotrypsin-coupled assay of the oligo-peptidyl substrate at 15�C. Besides this low PPIase activity, PhFKBP29 showed chaperone-like protein folding activity which enhanced the refolding yield of chemically unfolded rhodanese in vitro. In addition, it suppressed thermal protein aggregation in a temperature range of 45 to 100�C. When the PhFKBP29 gene was coexpressed with the recombinant Fab fragment gene of the anti-hen egg lysozyme antibody in the cytoplasm of E. coli, whose expressed product tended to form an inactive aggregate in E. coli, it improved the yield of the soluble Fab fragments with antibody specificity. PhFKBP29 exerted protein folding and aggregation suppression in E. coli cells.
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Kolos, Jürgen M., Sebastian Pomplun, Sascha Jung, Benedikt Rieß, Patrick L. Purder, Andreas M. Voll, Stephanie Merz, et al. "Picomolar FKBP inhibitors enabled by a single water-displacing methyl group in bicyclic [4.3.1] aza-amides." Chemical Science 12, no. 44 (2021): 14758–65. http://dx.doi.org/10.1039/d1sc04638a.

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Enhancement by displacement. A single methyl group displaces a water molecule from the binding site of FKBPs, resulting in the most potent binders known, outperforming the natural products FK506 and rapamycin in biochemical and cellular assays.
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Brizuela, L., G. Chrebet, K. A. Bostian, and S. A. Parent. "Antifungal properties of the immunosuppressant FK-506: identification of an FK-506-responsive yeast gene distinct from FKB1." Molecular and Cellular Biology 11, no. 9 (September 1991): 4616–26. http://dx.doi.org/10.1128/mcb.11.9.4616-4626.1991.

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FK-506 is a novel and potent antagonist of T-cell activation and an inhibitor of fungal growth. Its immunosuppressive activity can be antagonized by the structurally related antibiotic rapamycin, and both compounds interact with cytoplasmic FK-506-binding proteins (FKBPs) in T cells and yeast cells. In this paper, we show that FK-506 and two analogs inhibit vegetative growth of Saccharomyces cerevisiae in a fashion that parallels the immunosuppressive activity of these compounds. Yeast mutants resistant to FK-506 were isolated, and at least three complementation groups (fkr1, fkr2, and fkr3) were defined. These fkr mutants show no alteration in their levels of FK-506-binding activity. Likewise, strains carrying null alleles of FKB1 (the yeast gene coding for the FKBP) remain FK-506 sensitive, indicating that depletion of yeast FKBP is not sufficient to confer an FK-506 resistance phenotype, although fkb1 null mutants are resistant to rapamycin. FKB1 does not map to the three fkr loci defined here. These results suggest that yeast FKBP mediates the inhibitory effect of rapamycin but that at least one other protein is directly involved in mediating the activity of FK-506. Interestingly, the ability of FK-506 to rescue a temperature-sensitive growth defect of the fkr3 mutant suggests that the FKR3 gene may define such a protein.
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Brizuela, L., G. Chrebet, K. A. Bostian, and S. A. Parent. "Antifungal properties of the immunosuppressant FK-506: identification of an FK-506-responsive yeast gene distinct from FKB1." Molecular and Cellular Biology 11, no. 9 (September 1991): 4616–26. http://dx.doi.org/10.1128/mcb.11.9.4616.

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FK-506 is a novel and potent antagonist of T-cell activation and an inhibitor of fungal growth. Its immunosuppressive activity can be antagonized by the structurally related antibiotic rapamycin, and both compounds interact with cytoplasmic FK-506-binding proteins (FKBPs) in T cells and yeast cells. In this paper, we show that FK-506 and two analogs inhibit vegetative growth of Saccharomyces cerevisiae in a fashion that parallels the immunosuppressive activity of these compounds. Yeast mutants resistant to FK-506 were isolated, and at least three complementation groups (fkr1, fkr2, and fkr3) were defined. These fkr mutants show no alteration in their levels of FK-506-binding activity. Likewise, strains carrying null alleles of FKB1 (the yeast gene coding for the FKBP) remain FK-506 sensitive, indicating that depletion of yeast FKBP is not sufficient to confer an FK-506 resistance phenotype, although fkb1 null mutants are resistant to rapamycin. FKB1 does not map to the three fkr loci defined here. These results suggest that yeast FKBP mediates the inhibitory effect of rapamycin but that at least one other protein is directly involved in mediating the activity of FK-506. Interestingly, the ability of FK-506 to rescue a temperature-sensitive growth defect of the fkr3 mutant suggests that the FKR3 gene may define such a protein.
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Harrar, Yaël, Catherine Bellini, and Jean-Denis Faure. "FKBPs: at the crossroads of folding and transduction." Trends in Plant Science 6, no. 9 (September 2001): 426–31. http://dx.doi.org/10.1016/s1360-1385(01)02044-1.

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Romano, Maria Fiammetta. "FKBPs: opportunistic modifiers or active players in cancer?" Current Opinion in Pharmacology 11, no. 4 (August 2011): 279–80. http://dx.doi.org/10.1016/j.coph.2011.05.002.

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Ge, Qiang, Peipei Peng, Mingyue Cheng, Yanjun Meng, Yuan Cao, Shuya Zhang, Yu Long, Gezi Li, and Guozhang Kang. "Genome-Wide Identification and Analysis of FKBP Gene Family in Wheat (Triticum asetivum)." International Journal of Molecular Sciences 23, no. 23 (November 22, 2022): 14501. http://dx.doi.org/10.3390/ijms232314501.

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FK506-binding protein (FKBP) genes have been found to play vital roles in plant development and abiotic stress responses. However, limited information is available about this gene family in wheat (Triticum aestivum L.). In this study, a total of 64 FKBP genes were identified in wheat via a genome-wide analysis involving a homologous search of the latest wheat genome data, which was unevenly distributed in 21 chromosomes, encoded 152 to 649 amino acids with molecular weights ranging from 16 kDa to 72 kDa, and was localized in the chloroplast, cytoplasm, nucleus, mitochondria, peroxisome and endoplasmic reticulum. Based on sequence alignment and phylogenetic analysis, 64 TaFKBPs were divided into four different groups or subfamilies, providing evidence of an evolutionary relationship with Aegilops tauschii, Brachypodium distachyon, Triticum dicoccoides, Arabidopsis thaliana and Oryza sativa. Hormone-related, abiotic stress-related and development-related cis-elements were preferentially presented in promoters of TaFKBPs. The expression levels of TaFKBP genes were investigated using transcriptome data from the WheatExp database, which exhibited tissue-specific expression patterns. Moreover, TaFKBPs responded to drought and heat stress, and nine of them were randomly selected for validation by qRT-PCR. Yeast cells expressing TaFKBP19-2B-2 or TaFKBP18-6B showed increased influence on drought stress, indicating their negative roles in drought tolerance. Collectively, our results provide valuable information about the FKBP gene family in wheat and contribute to further characterization of FKBPs during plant development and abiotic stress responses, especially in drought stress.
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Caufield, C. E. "Structure-Activity Relationships Involving Modifications to The Macrolides FK-506 and Rapamycin." Current Pharmaceutical Design 1, no. 2 (September 1995): 145–60. http://dx.doi.org/10.2174/1381612801666220917215446.

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The purpose of this review is to introduce the reader to the biological characteristics of FK- 506 and rapamycin and to describe in detail the biological and synthetic transformations that have been applied to these compounds and their relationships to biological activity including modifications which affect binding to FKBPs and effector proteins.
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Romano, Simona, Anna D’Angelillo, and Maria Fiammetta Romano. "Pleiotropic roles in cancer biology for multifaceted proteins FKBPs." Biochimica et Biophysica Acta (BBA) - General Subjects 1850, no. 10 (October 2015): 2061–68. http://dx.doi.org/10.1016/j.bbagen.2015.01.004.

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Kageyama, Kazunori, Yasumasa Iwasaki, Yutaka Watanuki, Kanako Niioka, and Makoto Daimon. "Differential Effects of FKBP4 and FKBP5 on Regulation of the Proopiomelanocortin Gene in Murine AtT-20 Corticotroph Cells." International Journal of Molecular Sciences 22, no. 11 (May 27, 2021): 5724. http://dx.doi.org/10.3390/ijms22115724.

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The hypothalamic-pituitary-adrenal axis is stimulated in response to stress. When activated, it is suppressed by the negative feedback effect of glucocorticoids. Glucocorticoids directly inhibit proopiomelanocortin (Pomc) gene expression in the pituitary. Glucocorticoid signaling is mediated via glucocorticoid receptors, 11β-hydroxysteroid dehydrogenases, and the FK506-binding immunophilins, FKBP4 and FKBP5. FKBP4 and FKBP5 differentially regulate dynein interaction and nuclear translocation of the glucocorticoid receptor, resulting in modulation of the glucocorticoid action. Here, we explored the regulation of Fkbp4 and Fkbp5 genes and their proteins with dexamethasone, a major synthetic glucocorticoid drug, in murine AtT-20 corticotroph cells. To elucidate further roles of Fkbp4 and Fkbp5, we examined their effects on Pomc mRNA levels in corticotroph cells. Dexamethasone decreased Pomc mRNA levels as well as Fkpb4 mRNA levels in mouse corticotroph cells. Dexamethasone tended to decrease FKBP4 protein levels, while it increased Fkpb5 mRNA and its protein levels. The dexamethasone-induced decreases in Pomc mRNA levels were partially canceled by Fkbp4 knockdown. Alternatively, Pomc mRNA levels were further decreased by Fkbp5 knockdown. Thus, Fkbp4 contributes to the negative feedback of glucocorticoids, and Fkbp5 reduces the efficiency of the glucocorticoid effect on Pomc gene expression in pituitary corticotroph cells.
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Cheung, Ming-Yan, Wan-Kin Auyeung, Kwan-Pok Li, and Hon-Ming Lam. "A Rice Immunophilin Homolog, OsFKBP12, Is a Negative Regulator of Both Biotic and Abiotic Stress Responses." International Journal of Molecular Sciences 21, no. 22 (November 20, 2020): 8791. http://dx.doi.org/10.3390/ijms21228791.

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A class of proteins that were discovered to bind the immunosuppressant drug FK506, called FK506-binding proteins (FKBPs), are members of a sub-family of immunophilins. Although they were first identified in human, FKBPs exist in all three domains of life. In this report, a rice FKBP12 homolog was first identified as a biotic stress-related gene through suppression subtractive hybridization screening. By ectopically expressing OsFKBP12 in the heterologous model plant system, Arabidopsis thaliana, for functional characterization, OsFKBP12 was found to increase susceptibility of the plant to the pathogen, Pseudomonas syringae pv. tomato DC3000 (Pst DC3000). This negative regulatory role of FKBP12 in biotic stress responses was also demonstrated in the AtFKBP12-knockout mutant, which exhibited higher resistance towards Pst DC3000. Furthermore, this higher-plant FKBP12 homolog was also shown to be a negative regulator of salt tolerance. Using yeast two-hybrid tests, an ancient unconventional G-protein, OsYchF1, was identified as an interacting partner of OsFKBP12. OsYchF1 was previously reported as a negative regulator of both biotic and abiotic stresses. Therefore, OsFKBP12 probably also plays negative regulatory roles at the convergence of biotic and abiotic stress response pathways in higher plants.
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ZENG, Baifei, J. Randy MACDONALD, G. James BANN, Konrad BECK, E. Jay GAMBEE, A. Bruce BOSWELL, and Peter Hans BÄCHINGER. "Chicken FK506-binding protein, FKBP65, a member of the FKBP family of peptidylprolyl cis–trans isomerases, is only partially inhibited by FK506." Biochemical Journal 330, no. 1 (February 15, 1998): 109–14. http://dx.doi.org/10.1042/bj3300109.

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The chicken FK506-binding protein FKBP65, a peptidylprolyl cis-trans isomerase, is a rough endoplasmic reticulum protein that contains four domains homologous to FKBP13, another rough endoplasmic reticulum PPIase. Analytical ultracentrifugation suggests that in FKBP65 these four domains are arranged in a linear extended structure with a length of about 26 nm and a diameter of about 3 nm. All four domains are therefore expected to be accessible to substrates. The specificity of FKBP65 towards a number of peptide substrates was determined. The specific activity of FKBP65 is generally lower than that of FKBP12 when expressed as a per domain activity. The substrate specificity of FKBP65 also differs from that of FKBP12. Inhibition studies show that only one of the four domains can be inhibited by FK506, a powerful inhibitor of all other known FKBPs. Furthermore, the same domain seems to be susceptible to inhibition by cyclosporin A. No other FKBPs were shown to be inhibited by cyclosporin A. It is also shown that FKBP65 can catalyse the re-folding of type III collagen in vitro with a kcat/Km = 4.3×103 M-1·s-1.
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Fukuda, K., Y. Tanigawa, G. Fujii, S. Yasugi, and S. Hirohashi. "cFKBP/SMAP; a novel molecule involved in the regulation of smooth muscle differentiation." Development 125, no. 18 (September 15, 1998): 3535–42. http://dx.doi.org/10.1242/dev.125.18.3535.

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During embryogenesis, smooth muscle cells of the gut differentiate from mesenchymal cells derived from splanchnic mesoderm. We have isolated a gene involved in the differentiation of smooth muscle cells in the gut using differential display between the chicken proventriculus in which the smooth muscle layer develops poorly and the gizzard in which smooth muscles develop abundantly. The protein encoded by this gene showed highest similarity to mouse FK506 binding protein, FKBP65, and from the function of this protein it was designated chicken FKBP/smooth muscle activating protein (cFKBP/SMAP). cFKBP/SMAP was first expressed in smooth muscle precursor cells of the gut and, after smooth muscles differentiate, expression was restricted to smooth muscle cells. In organ culture of the gizzard, the differentiation of smooth muscle cells was inhibited by the addition of FK506, the inhibitor of FKBPs. Moreover, overexpression of cFKBP/SMAP in lung and gizzard mesenchymal cells induced smooth muscle differentiation. In addition, cFKBP/SMAP-induced smooth muscle differentiation was inhibited by FK506. We postulate therefore that cFKBP/SMAP plays a crucial role in smooth muscle differentiation in the gut and provides a powerful tool to study smooth muscle differentiation mechanisms, which have been poorly analyzed so far.
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Geisler, Markus, and Aurélien Bailly. "Tête-à-tête: the function of FKBPs in plant development." Trends in Plant Science 12, no. 10 (October 2007): 465–73. http://dx.doi.org/10.1016/j.tplants.2007.08.015.

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Park, Sang-Kyu, Haijie Xiao, and Ming Lei. "Nuclear FKBPs, Fpr3 and Fpr4 affect genome-wide genes transcription." Molecular Genetics and Genomics 289, no. 2 (December 3, 2013): 125–36. http://dx.doi.org/10.1007/s00438-013-0794-0.

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40

Orłowski, Marek, Katarzyna Popławska, Joanna Pieprzyk, Aleksandra Szczygieł-Sommer, Anna Więch, Mirosław Zarębski, Aneta Tarczewska, Jurek Dobrucki, and Andrzej Ożyhar. "Molecular determinants of Drosophila immunophilin FKBP39 nuclear localization." Biological Chemistry 399, no. 5 (April 25, 2018): 467–84. http://dx.doi.org/10.1515/hsz-2017-0251.

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AbstractFK506-binding proteins (FKBPs) belong to a distinct class of immunophilins that interact with immunosuppressants. They use their peptidyl-prolyl isomerase (PPIase) activity to catalyze thecis-transconversion of prolyl bonds in proteins during protein-folding events. FKBPs also act as a unique group of chaperones. TheDrosophila melanogasterpeptidyl-prolylcis-transisomerase FK506-binding protein of 39 kDa (FKBP39) is thought to act as a transcriptional modulator of gene expression in 20-hydroxyecdysone and juvenile hormone signal transduction. The aim of this study was to analyze the molecular determinants responsible for the subcellular distribution of an FKBP39-yellow fluorescent protein (YFP) fusion construct (YFP-FKBP39). We found that YFP-FKBP39 was predominantly nucleolar. To identify the nuclear localization signal (NLS), a series of YFP-tagged FKBP39 deletion mutants were prepared and examinedin vivo. The identified NLS signal is located in a basic domain. Detailed mutagenesis studies revealed that residues K188 and K191 are crucial for the nuclear targeting of FKBP39 and its nucleoplasmin-like (NPL) domain contains the sequence that controls the nucleolar-specific translocation of the protein. These results show that FKBP39 possesses a specific NLS in close proximity to a putative helix-turn-helix (HTH) motif and FKBP39 may bind DNAin vivoandin vitro.
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Marks, A. R. "Cellular functions of immunophilins." Physiological Reviews 76, no. 3 (July 1, 1996): 631–49. http://dx.doi.org/10.1152/physrev.1996.76.3.631.

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Immunophilins are members of a highly conserved family of proteins all of which are cis-trans peptidyl-prolyl isomerases. The prototypic members of the immunophilin family, cyclophilin A and FKPB12, were discovered on the basis of their ability to bind and mediate the immunosuppressive effects of the drugs cyclosporin, FK506, and rapamycin. However, the prolyl isomerase activity of these proteins is not involved in any of the immunosuppressive effects. Indeed, despite the fact that all members of the family are prolyl isomerases, the cellular role of this enzymatic function has not been clearly defined. In many cases, immunophilins are widely expressed and are present at high levels in some tissues. Moreover, while the number of proteins that belong to the immunophilin family continues to grow, the natural cellular functions of all but a few remain obscure. An example where immunophilins do appear to have a defined cellular role, in the absence of immunosuppressive ligands, is the modulation of intracellular calcium release channel function by FKBP12 and FKBP12.6. In this case, FKBPs are integral parts of three types of calcium release channel complexes, skeletal and cardiac ryanodine receptors and the inositol 1,4,5-trisphosphate receptor. In each case, FKBPs modulate channel function possibly by enhancing the cooperativity between subunits.
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Gudavicius, Geoff, Heddy Soufari, Santosh Upadhyay, Cameron D. Mackereth, and Christopher J. Nelson. "Resolving the functions of peptidylprolyl isomerases: insights from the mutagenesis of the nuclear FKBP25 enzyme." Biochemical Society Transactions 41, no. 3 (May 23, 2013): 761–68. http://dx.doi.org/10.1042/bst20130013.

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Peptidylprolyl isomerases have been implicated in chromatin regulation through their association with histones, chromatin-modifying enzymes and DNA-binding transcription factors. As with other post-translational modifications to proteins, a mechanistic understanding of the regulation of biological processes is fostered by loss-of-function studies both in vitro and in vivo. For peptidylprolyl isomerases, this can be accomplished with small-molecule inhibitors with high affinity for the isomerase active site or by mutation of amino acid residues that contribute to catalysis. In the present article, we review caveats to each of these approaches, and place emphasis on the thorough characterization of loss-of-function mutations in FKBPs (FK506-binding proteins). Using a case study of mutagenesis of the nuclear FKBP25 peptidylprolyl isomerase enzyme, we demonstrate that certain mutations generate a loss-of-function phenotype because they induce a complete loss of the FKBP domain fold, whereas other mutations are ‘surgical’ in that they ablate catalytic isomerase activity, while maintaining domain structure. Peptidylprolyl isomerases are thought to have both catalytic and non-catalytic functions, but differentiating between these mechanisms has proved to be challenging. The domain-destabilizing and surgical mutants described will facilitate the characterization of these two reported functions of peptidylprolyl isomerases.
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LENEGHAN, DARREN, and ANGUS BELL. "Immunophilin–protein interactions inPlasmodium falciparum." Parasitology 142, no. 11 (July 9, 2015): 1404–14. http://dx.doi.org/10.1017/s0031182015000803.

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SUMMARYImmunophilins comprise two protein families, cyclophilins (CYPs) and FK506-binding proteins (FKBPs), and are the major receptors for the immunosuppressive drugs cyclosporin A (CsA) and FK506 (tacrolimus), respectively. Most eukaryotic species have at least one immunophilin and some of them have been associated with pathogenesis of infectious or parasitic diseases or the action of antiparasitic drugs. The human malarial parasitePlasmodium falciparumhas 13 immunophilin or immunophilin-like genes but the functions of their products are unknown. We set out to identify the parasite proteins that interact with the major CYPs, PfCYP19A and PfCYP19B, and the FKBP, PfFKBP35, using a combination of co-immunoprecipitation and yeast two-hybrid screening. We identified a cohort of putative interacting partners and further investigation of some of these revealed potentially novel roles in parasite biology. We demonstrated that (i)P. falciparumCYPs interacted with the heat shock protein 70, (ii) treatment of parasites with CYP ligands disrupted transport of the rhoptry-associated protein 1, and (iii) PfFKBP35 interacted with parasite histones in a way that might modulate gene expression. These findings begin to elucidate the functions of immunophilins in malaria. Furthermore, the known antimalarial effects of CsA, FK506 and non-immunosuppressive derivatives of these immunophilin ligands could be mediated through these partner proteins.
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44

Geisler, Markus, H. Üner Kolukisaoglu, Rodolphe Bouchard, Karla Billion, Joachim Berger, Beate Saal, Nathalie Frangne, et al. "TWISTED DWARF1, a Unique Plasma Membrane-anchored Immunophilin-like Protein, Interacts with Arabidopsis Multidrug Resistance-like Transporters AtPGP1 and AtPGP19." Molecular Biology of the Cell 14, no. 10 (October 2003): 4238–49. http://dx.doi.org/10.1091/mbc.e02-10-0698.

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Null-mutations of the Arabidopsis FKBP-like immunophilin TWISTED DWARF1 (TWD1) gene cause a pleiotropic phenotype characterized by reduction of cell elongation and disorientated growth of all plant organs. Heterologously expressed TWD1 does not exhibit cis-trans-peptidylprolyl isomerase (PPIase) activity and does not complement yeast FKBP12 mutants, suggesting that TWD1 acts indirectly via protein-protein interaction. Yeast two-hybrid protein interaction screens with TWD1 identified cDNA sequences that encode the C-terminal domain of Arabidopsis multidrugresistance-like ABC transporter AtPGP1. This interaction was verified in vitro. Mapping of protein interaction domains shows that AtPGP1 surprisingly binds to the N-terminus of TWD1 harboring the cis-trans peptidyl-prolyl isomerase-like domain and not to the tetratrico-peptide repeat domain, which has been shown to mediate protein-protein interaction. Unlike all other FKBPs, TWD1 is shown to be an integral membrane protein that colocalizes with its interacting partner AtPGP1 on the plasma membrane. TWD1 also interacts with AtPGP19 (AtMDR1), the closest homologue of AtPGP1. The single gene mutation twd1-1 and double atpgp1-1/atpgp19-1 (atmdr1-1) mutants exhibit similar phenotypes including epinastic growth, reduced inflorescence size, and reduced polar auxin transport, suggesting that a functional TWD1-AtPGP1/AtPGP19 complex is required for proper plant development.
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45

Galat, Andrzej. "Functional Drift of Sequence Attributes in the FK506-Binding Proteins (FKBPs)." Journal of Chemical Information and Modeling 48, no. 5 (April 16, 2008): 1118–30. http://dx.doi.org/10.1021/ci700429n.

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46

Geisler, Markus, Aurélien Bailly, and Maria Ivanchenko. "Master and servant: Regulation of auxin transporters by FKBPs and cyclophilins." Plant Science 245 (April 2016): 1–10. http://dx.doi.org/10.1016/j.plantsci.2015.12.004.

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47

Zarnt, T., K. Lang, H. Burtscher, and G. Fischer. "Time-dependent inhibition of peptidylprolyl cis-trans-isomerases by FK506 is probably due to cis-trans isomerization of the inhibitor's imide bond." Biochemical Journal 305, no. 1 (January 1, 1995): 159–64. http://dx.doi.org/10.1042/bj3050159.

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Free in solution, the immunosuppressive compounds cyclosporin A (CsA), FK506, ascomycin and rapamycin are present in many solvents in various slowly interconverting conformations. Together with their cellular receptor proteins, cyclophilin (CyP) and FK506-binding protein (FKBP), however, these inhibitors have been shown to have a homogeneous conformation. The existence of a slow cis-trans interconversion of an imidic bond in the inhibitor molecule during the course of the formation of the CsA-CyP18cy complex (where CyP18cy is human 18 kDa cytosolic CyP) prompted us to investigate the reaction of the peptidomacrolides FK506, ascomycin and rapamycin with two specific binding-proteins in more detail. Since formation of the FK506-FKBP complex results in the inhibition of the peptidylprolyl cis-trans-isomerase activity of the binding protein, we used the enzyme's decrease in enzymic activity to monitor binding of the inhibitors to their enzyme targets. For FK506, the kinetics of inhibition of human 12 kDa cytosolic FKBP (FKBP12cy) were clearly dependent on time. Subsequent to a rapid inactivation reaction, not resolved in its kinetics due to manual mixing, a slow dominant first-order inactivation process with a relaxation time of 1163 s at 10 degrees C was observed. Concomitantly the Ki value of the slow phase dropped 2.6-fold within the first 60 min of incubation. Using the FKBP12cy homologue 25 kDa membrane FKBP (FKBP25mem), a bacterial peptidylprolyl cis-trans-isomerase, the rate and amplitudes of the inhibition reactions were very similar to FKBP12cy. On the other hand, the kinetics and amplitudes of the inhibition of FKBP12cy varied significantly if rapamycin was used as an inhibitor instead of FK 506. Owing to reduced conformation transition in rapamycin upon binding to FKBP12cy, the slow phase during inhibition was significantly decreased in amplitude. A likely reason for this became apparent when the activation-enthalpy and the pH-dependence of the rate constants of the slow phase were determined. We conclude that the cis to trans interconversion of the pipecolinyl bond of the three peptidomacrolides may be responsible for the slow process. There was no indication of a suicide catalysis of this process by FKBPs.
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48

Pemberton, Trevor J., and John E. Kay. "Identification and Comparative Analysis of the Peptidyl-Prolylcis/transIsomerase Repertoires ofH. sapiens, D. melanogaster, C. elegans, S. cerevisiae and Sz. pombe." Comparative and Functional Genomics 6, no. 5-6 (2005): 277–300. http://dx.doi.org/10.1002/cfg.482.

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The peptidyl-prolylcis/transisomerase (PPIase) class of proteins comprises three member families that are found throughout nature and are present in all the major compartments of the cell. Their numbers appear to be linked to the number of genes in their respective genomes, although we have found the human repertoire to be smaller than expected due to a reduced cyclophilin repertoire. We show here that whilst the members of the cyclophilin family (which are predominantly found in the nucleus and cytoplasm) and the parvulin family (which are predominantly nuclear) are largely conserved between different repertoires, the FKBPs (which are predominantly found in the cytoplasm and endoplasmic reticulum) are not. It therefore appears that the cyclophilins and parvulins have evolved to perform conserved functions, while the FKBPs have evolved to fill ever-changing niches within the constantly evolving organisms. Many orthologous subgroups within the different PPIase families appear to have evolved from a distinct common ancestor, whereas others, such as the mitochondrial cyclophilins, appear to have evolved independently of one another. We have also identified a novel parvulin withinDrosophila melanogasterthat is unique to the fruit fly, indicating a recent evolutionary emergence. Interestingly, the fission yeast repertoire, which contains no unique cyclophilins and parvulins, shares no PPIases solely with the budding yeast but it does share a majority with the higher eukaryotes in this study, unlike the budding yeast. It therefore appears that, in comparison withSchizosaccharomyces pombe, Saccharomyces cerevisiaeis a poor representation of the higher eukaryotes for the study of PPIases.
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Hähle, Andreas, Stephanie Merz, Christian Meyners, and Felix Hausch. "The Many Faces of FKBP51." Biomolecules 9, no. 1 (January 21, 2019): 35. http://dx.doi.org/10.3390/biom9010035.

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The FK506-binding protein 51 (FKBP51) has emerged as a key regulator of endocrine stress responses in mammals and as a potential therapeutic target for stress-related disorders (depression, post-traumatic stress disorder), metabolic disorders (obesity and diabetes) and chronic pain. Recently, FKBP51 has been implicated in several cellular pathways and numerous interacting protein partners have been reported. However, no consensus on the underlying molecular mechanisms has yet emerged. Here, we review the protein interaction partners reported for FKBP51, the proposed pathways involved, their relevance to FKBP51’s physiological function(s), the interplay with other FKBPs, and implications for the development of FKBP51-directed drugs.
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50

Pomplun, Sebastian, Yansong Wang, Alexander Kirschner, Christian Kozany, Andreas Bracher, and Felix Hausch. "Rationales Design und asymmetrische Synthese potenter neuritotropher Liganden für FK506-bindende Proteine (FKBPs)." Angewandte Chemie 127, no. 1 (November 24, 2014): 352–55. http://dx.doi.org/10.1002/ange.201408776.

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