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Journal articles on the topic 'Targeting signal'

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Published: 4 June 2025
Last updated: 7 July 2025

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1

Weber, George, Fei Shen, Tamás I. Orbán, Szabolcs Kökeny, and Edith Olah. "Targeting signal transduction." Advances in Enzyme Regulation 43, no. 1 (2003): 47–56. http://dx.doi.org/10.1016/s0065-2571(03)00021-9.

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2

Bertino, Joseph R. "Targeting signal transduction." Current Oncology Reports 3, no. 6 (2001): 453–54. http://dx.doi.org/10.1007/s11912-001-0063-y.

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3

Beeram, Muralidhar, and Amita Patnaik. "Targeting intracellular signal transduction." Hematology/Oncology Clinics of North America 16, no. 5 (2002): 1089–100. http://dx.doi.org/10.1016/s0889-8588(02)00054-0.

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4

Varshavsky, Alexander. "Naming a targeting signal." Cell 64, no. 1 (1991): 13–15. http://dx.doi.org/10.1016/0092-8674(91)90202-a.

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5

Gould, S. J., G. A. Keller, and S. Subramani. "Identification of peroxisomal targeting signals located at the carboxy terminus of four peroxisomal proteins." Journal of Cell Biology 107, no. 3 (1988): 897–905. http://dx.doi.org/10.1083/jcb.107.3.897.

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As part of an effort to understand how proteins are imported into the peroxisome, we have sought to identify the peroxisomal targeting signals in four unrelated peroxisomal proteins: human catalase, rat hydratase:dehydrogenase, pig D-amino acid oxidase, and rat acyl-CoA oxidase. Using gene fusion experiments, we have identified a region of each protein that can direct heterologous proteins to peroxisomes. In each case, the peroxisomal targeting signal is contained at or near the carboxy terminus of the protein. For catalase, the peroxisomal targeting signal is located within the COOH-terminal 27 amino acids of the protein. For hydratase:dehydrogenase, D-amino acid oxidase, and acyl-CoA oxidase, the targeting signals are located within the carboxy-terminal 15, 14, and 15 amino acids, respectively. A tripeptide of the sequence Ser-Lys/His-Leu is present in each of these targeting signals as well as in the peroxisomal targeting signal identified in firefly luciferase (Gould, S.J., G.-A. Keller, and S. Subramani. 1987. J. Cell Biol. 105:2923-2931). When the peroxisomal targeting signal of the hydratase:dehydrogenase is mutated so that the Ser-Lys-Leu tripeptide is converted to Ser-Asn-Leu, it can no longer direct proteins to peroxisomes. We suggest that this tripeptide is an essential element of at least one class of peroxisomal targeting signals.
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6

Chatzi, Katerina E., Marios Frantzeskos Sardis, Alexandra Tsirigotaki, et al. "Preprotein mature domains contain translocase targeting signals that are essential for secretion." Journal of Cell Biology 216, no. 5 (2017): 1357–69. http://dx.doi.org/10.1083/jcb.201609022.

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Secretory proteins are only temporary cytoplasmic residents. They are typically synthesized as preproteins, carrying signal peptides N-terminally fused to their mature domains. In bacteria secretion largely occurs posttranslationally through the membrane-embedded SecA-SecYEG translocase. Upon crossing the plasma membrane, signal peptides are cleaved off and mature domains reach their destinations and fold. Targeting to the translocase is mediated by signal peptides. The role of mature domains in targeting and secretion is unclear. We now reveal that mature domains harbor their own independent targeting signals (mature domain targeting signals [MTSs]). These are multiple, degenerate, interchangeable, linear or 3D hydrophobic stretches that become available because of the unstructured states of targeting-competent preproteins. Their receptor site on the cytoplasmic face of the SecYEG-bound SecA is also of hydrophobic nature and is located adjacent to the signal peptide cleft. Both the preprotein MTSs and their receptor site on SecA are essential for protein secretion. Evidently, mature domains have their own previously unsuspected distinct roles in preprotein targeting and secretion.
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7

Gould, S. G., G. A. Keller, and S. Subramani. "Identification of a peroxisomal targeting signal at the carboxy terminus of firefly luciferase." Journal of Cell Biology 105, no. 6 (1987): 2923–31. http://dx.doi.org/10.1083/jcb.105.6.2923.

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Translocation of proteins across membranes of the endoplasmic reticulum, mitochondrion, and chloroplast has been shown to be mediated by targeting signals present in the transported proteins. To test whether the transport of proteins into peroxisomes is also mediated by a peptide targeting signal, we have studied the firefly luciferase gene that encodes a protein transported to peroxisomes in both insect and mammalian cells. We have identified two regions of luciferase which are necessary for transport of this protein into peroxisomes. We demonstrate that one of these, region II, represents a peroxisomal targeting signal because it is both necessary and sufficient for directing cytosolic proteins to peroxisomes. The signal is no more than twelve amino acids long and is located at the extreme carboxy-terminus of luciferase. The location of the targeting signal for translocation across the peroxisomal membrane therefore differs from the predominantly amino-terminal location of signals responsible for transport across the membranes of the endoplasmic reticulum, chloroplast, or mitochondrion.
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8

Ellis, S. R., A. K. Hopper, and N. C. Martin. "Amino-terminal extension generated from an upstream AUG codon increases the efficiency of mitochondrial import of yeast N2,N2-dimethylguanosine-specific tRNA methyltransferases." Molecular and Cellular Biology 9, no. 4 (1989): 1611–20. http://dx.doi.org/10.1128/mcb.9.4.1611-1620.1989.

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Fusions between the TRM1 gene of Saccharomyces cerevisiae and COXIV or DHFR were made to examine the mitochondrial targeting signals of N2,N2-dimethylguanosine-specific tRNA methyltransferase [tRNA (m2(2)G)dimethyltransferase]. This enzyme is responsible for the modification of both mitochondrial and cytoplasmic tRNAs. We have previously shown that two forms of the enzyme are translated from two in-frame ATGs in this gene, that they differ by a 16-amino-acid amino-terminal extension, and that both the long and short forms are imported into mitochondria. Results of studies to test the ability of various TRM1 sequences to serve as surrogate mitochondrial targeting signals for passenger protein import in vitro and in vivo showed that the most efficient signal derived from tRNA (m2(2)G)dimethyltransferase included a combination of sequences from both the amino-terminal extension and the amino terminus of the shorter form of the enzyme. The amino-terminal extension itself did not serve as an independent mitochondrial targeting signal, whereas the amino terminus of the shorter form of tRNA (m2(2)G)dimethyltransferase did function in this regard, albeit inefficiently. We analyzed the first 48 amino acids of tRNA (m2(2)G)dimethyltransferase for elements of primary and secondary structure shared with other known mitochondrial targeting signals. The results lead us to propose that the most efficient signal spans the area around the second ATG of TRM1 and is consistent with the idea that there is a mitochondrial targeting signal present at the amino terminus of the shorter form of the enzyme and that the amino-terminal extension augments this signal by extending it to form a larger, more efficient mitochondrial targeting signal.
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9

Ellis, S. R., A. K. Hopper, and N. C. Martin. "Amino-terminal extension generated from an upstream AUG codon increases the efficiency of mitochondrial import of yeast N2,N2-dimethylguanosine-specific tRNA methyltransferases." Molecular and Cellular Biology 9, no. 4 (1989): 1611–20. http://dx.doi.org/10.1128/mcb.9.4.1611.

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Fusions between the TRM1 gene of Saccharomyces cerevisiae and COXIV or DHFR were made to examine the mitochondrial targeting signals of N2,N2-dimethylguanosine-specific tRNA methyltransferase [tRNA (m2(2)G)dimethyltransferase]. This enzyme is responsible for the modification of both mitochondrial and cytoplasmic tRNAs. We have previously shown that two forms of the enzyme are translated from two in-frame ATGs in this gene, that they differ by a 16-amino-acid amino-terminal extension, and that both the long and short forms are imported into mitochondria. Results of studies to test the ability of various TRM1 sequences to serve as surrogate mitochondrial targeting signals for passenger protein import in vitro and in vivo showed that the most efficient signal derived from tRNA (m2(2)G)dimethyltransferase included a combination of sequences from both the amino-terminal extension and the amino terminus of the shorter form of the enzyme. The amino-terminal extension itself did not serve as an independent mitochondrial targeting signal, whereas the amino terminus of the shorter form of tRNA (m2(2)G)dimethyltransferase did function in this regard, albeit inefficiently. We analyzed the first 48 amino acids of tRNA (m2(2)G)dimethyltransferase for elements of primary and secondary structure shared with other known mitochondrial targeting signals. The results lead us to propose that the most efficient signal spans the area around the second ATG of TRM1 and is consistent with the idea that there is a mitochondrial targeting signal present at the amino terminus of the shorter form of the enzyme and that the amino-terminal extension augments this signal by extending it to form a larger, more efficient mitochondrial targeting signal.
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10

Liu, Xingyi. "De-targeting to signal quality." International Journal of Research in Marketing 37, no. 2 (2020): 386–404. http://dx.doi.org/10.1016/j.ijresmar.2019.10.003.

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11

Kragler, F., A. Langeder, J. Raupachova, M. Binder, and A. Hartig. "Two independent peroxisomal targeting signals in catalase A of Saccharomyces cerevisiae." Journal of Cell Biology 120, no. 3 (1993): 665–73. http://dx.doi.org/10.1083/jcb.120.3.665.

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In contrast to many other peroxisomal proteins catalase A contains at least two peroxisomal targeting signals each sufficient to direct reporter proteins to peroxisomes. One of them resides at the extreme carboxy terminus constituting a new variant of this signal, -SSNSKF, not active in monkey kidney cells (Gould, S. J., G. A. Keller, N. Hosken, J. Wilkinson, and S. Subramani 1989. J. Cell Biol. 108:1657-1664). However, this signal is completely dispensable for import of catalase A itself. In its amino-terminal third this protein contains another peroxisomal targeting signal sufficient to direct reporter proteins into microbodies. This internal signal depends on the context. The nature of this targeting signal might be a short defined sequence or a structural feature recognized by import factors. In addition, we have demonstrated that the carboxy-terminal seven amino acids of citrate synthase of Saccharomyces cerevisiae encoded by CIT2 and containing the canonical -SKL represents a targeting signal sufficient to direct reporter proteins to peroxisomes.
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12

Goder, Veit, Christoph Bieri, and Martin Spiess. "Glycosylation Can Influence Topogenesis of Membrane Proteins and Reveals Dynamic Reorientation of Nascent Polypeptides within the Translocon." Journal of Cell Biology 147, no. 2 (1999): 257–66. http://dx.doi.org/10.1083/jcb.147.2.257.

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The topology of multispanning membrane proteins in the mammalian endoplasmic reticulum is thought to be dictated primarily by the first hydrophobic sequence. We analyzed the in vivo insertion of a series of chimeric model proteins containing two conflicting signal sequences, i.e., an NH2-terminal and an internal signal, each of which normally directs translocation of its COOH-terminal end. When the signals were separated by more than 60 residues, linear insertion with the second signal acting as a stop-transfer sequence was observed. With shorter spacers, an increasing fraction of proteins inserted with a translocated COOH terminus as dictated by the second signal. Whether this resulted from membrane targeting via the second signal was tested by measuring the targeting efficiency of NH2-terminal signals followed by polypeptides of different lengths. The results show that targeting is mediated predominantly by the first signal in a protein. Most importantly, we discovered that glycosylation within the spacer sequence affects protein orientation. This indicates that the nascent polypeptide can reorient within the translocation machinery, a process that is blocked by glycosylation. Thus, topogenesis of membrane proteins is a dynamic process in which topogenic information of closely spaced signal and transmembrane sequences is integrated.
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13

Chew, Orinda, and James Whelan. "Dual targeting ability of targeting signals is dependent on the nature of the mature protein." Functional Plant Biology 30, no. 7 (2003): 805. http://dx.doi.org/10.1071/fp03077.

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The targeting ability of three signals previously shown to support the import of passenger proteins into both mitochondria and chloroplasts was investigated with authentic mitochondrial or chloroplastic proteins. An in vitro dual import assay that maintained import specificity showed that the ability of dual signals to support mitochondrial and chloroplastic import depended on the nature of the passenger protein. All dual targeting signals supported import of their native mature protein as a passenger into both mitochondria and chloroplasts. However the glutathione reductase targeting signal only supported mitochondrial import with the mitochondrial protein alternative oxidase, and chloroplast import with the small subunit of ribulose-1,5-bisphosphate carboxylase / oxygenase. The Arabidopsis histidyl-tRNA synthetase targeting signal only supported mitochondrial import with the alternative oxidase as a passenger, but the small subunit of ribulose-1,5-bisphosphate carboxylase / oxygenase was imported into both mitochondria and chloroplasts. The Arabidopsis asparaginyl-tRNA synthetase supported import of alternative oxidase and the small subunit of ribulose-1,5-bisphosphate carboxylase / oxygenase into both mitochondria and chloroplasts. Analysis of the targeting signals of all known dual targeted proteins using targeting predictions indicates that most of them are more strongly predicted to be chloroplast-targeted. Secondary structure predictions indicate the ability of most dual targeted signals to form both α-helical and β-sheet-type structures, a feature of mitochondrial and plastid targeting signals, respectively. Thus, it appears that a major determinant of dual targeting ability is the nature of the mature or passenger protein.
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14

Kitoh, Yoshihiro, Hitoshi Ueda, Takashi Andoh, Noriaki Yokoi, and Katuto Takemura. "426 MR Angiography using Signal Targeting with Alternating Radiofrequency(STAR)." Japanese Journal of Radiological Technology 53, no. 8 (1997): 1296. http://dx.doi.org/10.6009/jjrt.kj00001356267.

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15

McCubrey, James A., Linda S. Steelman, William H. Chappell, et al. "Advances in Targeting Signal Transduction Pathways." Oncotarget 3, no. 12 (2012): 1505–21. http://dx.doi.org/10.18632/oncotarget.802.

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16

Stroud, Robert M., and Peter Walter. "Signal sequence recognition and protein targeting." Current Opinion in Structural Biology 9, no. 6 (1999): 754–59. http://dx.doi.org/10.1016/s0959-440x(99)00040-8.

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17

Levitzki, Alexander. "Targeting signal transduction for disease therapy." Current Opinion in Cell Biology 8, no. 2 (1996): 239–44. http://dx.doi.org/10.1016/s0955-0674(96)80071-8.

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18

Levitzki, Alexander. "Targeting signal transduction for disease therapy." Medical Oncology 14, no. 2 (1997): 83–89. http://dx.doi.org/10.1007/bf02990952.

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19

Kunze, Markus. "The type-2 peroxisomal targeting signal." Biochimica et Biophysica Acta (BBA) - Molecular Cell Research 1867, no. 2 (2020): 118609. http://dx.doi.org/10.1016/j.bbamcr.2019.118609.

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20

Flaherty, K. T. "Targeting signal transduction pathways in melanoma." Melanoma Research 20 (June 2010): e20. http://dx.doi.org/10.1097/01.cmr.0000382784.44182.71.

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21

Dillon, Christian, Anna Creer, Karen Kerr, Angelika Kümin, and Clive Dickson. "Basolateral Targeting of ERBB2 Is Dependent on a Novel Bipartite Juxtamembrane Sorting Signal but Independent of the C-Terminal ERBIN-Binding Domain." Molecular and Cellular Biology 22, no. 18 (2002): 6553–63. http://dx.doi.org/10.1128/mcb.22.18.6553-6563.2002.

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ABSTRACT ERBB2 is a receptor tyrosine kinase present on the basolateral membrane of polarized epithelia and has important functions in organ development and tumorigenesis. Using mutagenic analyses and Madin-Darby canine kidney (MDCK) cells, we have investigated the signals that regulate basolateral targeting of ERBB2. We show that basolateral delivery of ERBB2 is dependent on a novel bipartite juxtamembrane sorting signal residing between Gln-692 and Thr-701. The signal shows only limited sequence homology to known basolateral targeting signals and is both necessary and sufficient for correct sorting of ERBB2. In addition we demonstrate that this motif can function as a dominant basolateral targeting signal by its ability to redirect the apically localized P75 neurotrophin receptor to the basolateral membrane domain of polarized epithelial cells. Interestingly, LLC-PK1 cells, which are deficient for the μ1B subunit of the AP1B adaptor complex, missort a large proportion of ERBB2 to the apical membrane domain. This missorting can be partially corrected by the introduction of μ1B, suggesting a possible role for AP1B in ERBB2 endosomal trafficking. Furthermore, we find that the C-terminal ERBIN binding domain of ERBB2 is not necessary for its basolateral targeting in MDCK cells.
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22

Dworetzky, S. I., R. E. Lanford, and C. M. Feldherr. "The effects of variations in the number and sequence of targeting signals on nuclear uptake." Journal of Cell Biology 107, no. 4 (1988): 1279–87. http://dx.doi.org/10.1083/jcb.107.4.1279.

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To determine if the number of targeting signals affects the transport of proteins into the nucleus, Xenopus oocytes were injected with colloidal gold particles, ranging in diameter from 20 to 280 A, that were coated with BSA cross-linked with synthetic peptides containing the SV-40 large T-antigen nuclear transport signal. Three BSA conjugate preparations were used; they had an average of 5, 8, and 11 signals per molecule of carrier protein. In addition, large T-antigen, which contains one signal per monomer, was used as a coating agent. The cells were fixed at various times after injection and subsequently analyzed by electron microscopy. Gold particles coated with proteins containing the SV-40 signal entered the nucleus through central channels located within the nuclear pores. Analysis of the intracellular distribution and size of the tracers that entered the nucleus indicated that the number of signals per molecule affect both the relative uptake of particles and the functional size of the channels available for translocation. In control experiments, gold particles coated with BSA or BSA conjugated with inactive peptides similar to the SV-40 transport signal were virtually excluded from the nucleus. Gold particles coated with nucleoplasmin, an endogenous karyophilic protein that contains five targeting signals per molecule, was transported through the nuclear pores more effectively than any of the BSA-peptide conjugates. Based on a correlation between the peri-envelope density of gold particles and their relative uptake, it is suggested that the differences in the activity of the two targeting signals is related to their binding affinity for envelope receptors. It was also determined, by performing coinjection experiments, that individual pores are capable of recognizing and transporting proteins that contain different nuclear targeting signals.
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23

Chen, Hua, and Xue Ting Zhang. "The Comparison Study of Targeting Observation for Extratropical Transition of Hurricane Fabian." Advanced Materials Research 518-523 (May 2012): 5840–45. http://dx.doi.org/10.4028/www.scientific.net/amr.518-523.5840.

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This study compares the propagation methods of the impact of targeted observations during the extratropical transition (ET) of Hurricane Fabian in three denial experiments. In sensitive experiment, the signal (forecast difference between denial experiments and control) propagates from the tropical cyclone (TC) to the midlatitude jet through the interaction between the TC and the jet itself. Thereafter, signals propagate eastward along the jet by way of Rossby wave packets. Some differences exist between random/Atlantic and sensitive experiment although many of their signal propagation characteristics are similar. The signal in random experiment is the weakest, and that in Atlantic experiment is the strongest. In Atlantic experiment, initial signals appear not only in Fabian, but also in other regions. In some cases, signals even do not appear in Fabian. Its propagation method is similar to that in sensitive and random experiment except some signals exist at ridges occasionally. From the discussion above, we conclude that targeted observations have more positive impact than random observations, but can not replace observations taken in the whole Atlantic.
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24

Matter, K., E. M. Yamamoto, and I. Mellman. "Structural requirements and sequence motifs for polarized sorting and endocytosis of LDL and Fc receptors in MDCK cells." Journal of Cell Biology 126, no. 4 (1994): 991–1004. http://dx.doi.org/10.1083/jcb.126.4.991.

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In MDCK cells, basolateral sorting of most membrane proteins has been shown to depend on distinct cytoplasmic domain determinants. These signals can be divided into those which are related to signals for localization at clathrin-coated pits and those which are unrelated. The LDL receptor bears two tyrosine-containing signals, one of each class, that can independently target receptors from the Golgi complex and from endosomes to the basolateral plasma membrane. We have now investigated the other structural features required for the activity of both determinants. We find that both depend, at least in part, on clusters of 1-3 acidic amino acids located on the COOH-terminal side of each tyrosine. While single residues adjacent to each tyrosine were also found to be critical, the two signals differed in that only the coated pit-unrelated signal could tolerate a phenylalanine in place of its tyrosine residue. We also found that the structural requirements for basolateral targeting of the "coated pit-related" signal were distinct from those required for rapid endocytosis. Apart from sharing a common tyrosine residue, no feature of the NPXY motif for coated pit localization was required for basolateral targeting. We also investigated basolateral targeting of the mouse macrophage Fc receptor (FcRII-B2) which contains a tyrosine-independent coated pit localization signal. Basolateral transport and endocytosis were found to depend on a common dileucine-type motif. Thus, basolateral targeting determinants, like coated pit domains, can contain either tyrosine- or di-leucine-containing signals. The amino acids in the vicinity of these motifs determine whether they function as determinants for endocytosis, basolateral targeting, or both.
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25

Kanaani, Jamil, Alaa El-Din El-Husseini, Andrea Aguilera-Moreno, Julia M. Diacovo, David S. Bredt, and Steinunn Baekkeskov. "A combination of three distinct trafficking signals mediates axonal targeting and presynaptic clustering of GAD65." Journal of Cell Biology 158, no. 7 (2002): 1229–38. http://dx.doi.org/10.1083/jcb.200205053.

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The signals involved in axonal trafficking and presynaptic clustering are poorly defined. Here we show that targeting of the γ-aminobutyric acid–synthesizing enzyme glutamate decarboxylase 65 (GAD65) to presynaptic clusters is mediated by its palmitoylated 60-aa NH2-terminal domain and that this region can target other soluble proteins and their associated partners to presynaptic termini. A Golgi localization signal in aa 1–23 followed by a membrane anchoring signal upstream of the palmitoylation motif are required for this process and mediate targeting of GAD65 to the cytosolic leaflet of Golgi membranes, an obligatory first step in axonal sorting. Palmitoylation of a third trafficking signal downstream of the membrane anchoring signal is not required for Golgi targeting. However, palmitoylation of cysteines 30 and 45 is critical for post-Golgi trafficking of GAD65 to presynaptic sites and for its relative dendritic exclusion. Reduction of cellular cholesterol levels resulted in the inhibition of presynaptic clustering of palmitoylated GAD65, suggesting that the selective targeting of the protein to presynaptic termini is dependent on sorting to cholesterol-rich membrane microdomains. The palmitoylated NH2-terminal region of GAD65 is the first identified protein region that can target other proteins to presynaptic clusters.
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Michaelson, David, Ian Ahearn, Martin Bergo, Stephen Young, and Mark Philips. "Membrane Trafficking of Heterotrimeric G Proteins via the Endoplasmic Reticulum and Golgi." Molecular Biology of the Cell 13, no. 9 (2002): 3294–302. http://dx.doi.org/10.1091/mbc.e02-02-0095.

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Membrane targeting of G-protein αβγ heterotrimers was investigated in live cells by use of Gα and Gγ subunits tagged with spectral mutants of green fluorescent protein. Unlike Ras proteins, Gβγ contains a single targeting signal, the CAAX motif, which directed the dimer to the endoplasmic reticulum. Endomembrane localization of farnesylated Gγ1, but not geranylgeranylated Gγ2, required carboxyl methylation. Targeting of the heterotrimer to the plasma membrane (PM) required coexpression of all three subunits, combining the CAAX motif of Gγ with the fatty acyl modifications of Gα. Gα associated with Gβγ on the Golgi and palmitoylation of Gα was required for translocation of the heterotrimer to the PM. Thus, two separate signals, analogous to the dual-signal targeting mechanism of Ras proteins, cooperate to target heterotrimeric G proteins to the PM via the endomembrane.
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Jomaa, Ahmad, Martin Gamerdinger, Hao-Hsuan Hsieh, et al. "Mechanism of signal sequence handover from NAC to SRP on ribosomes during ER-protein targeting." Science 375, no. 6583 (2022): 839–44. http://dx.doi.org/10.1126/science.abl6459.

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The nascent polypeptide–associated complex (NAC) interacts with newly synthesized proteins at the ribosomal tunnel exit and competes with the signal recognition particle (SRP) to prevent mistargeting of cytosolic and mitochondrial polypeptides to the endoplasmic reticulum (ER). How NAC antagonizes SRP and how this is overcome by ER targeting signals are unknown. Here, we found that NAC uses two domains with opposing effects to control SRP access. The core globular domain prevented SRP from binding to signal-less ribosomes, whereas a flexibly attached domain transiently captured SRP to permit scanning of nascent chains. The emergence of an ER-targeting signal destabilized NAC’s globular domain and facilitated SRP access to the nascent chain. These findings elucidate how NAC hands over the signal sequence to SRP and imparts specificity of protein localization.
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Zhuang, Zhan, Jinglin Zhou, Minglian Qiu, et al. "The Combination of Anti-CD47 Antibody with CTLA4 Blockade Enhances Anti-Tumor Immunity in Non-Small Cell Lung Cancer via Normalization of Tumor Vasculature and Reprogramming of the Immune Microenvironment." Cancers 16, no. 4 (2024): 832. http://dx.doi.org/10.3390/cancers16040832.

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In solid tumors, the formidable anti-tumor impact resulting from blocking the “don’t eat me” signal, arising from CD47–SIRPα interaction, is constrained, especially compared to its efficacy in hematopoietic malignancies. Activating macrophage anti-tumor activity not only necessitates the inhibition of the “don’t eat me” signal, but also the activation of the “eat me” (pre-phagocyte) signal. Intriguingly, the cytotoxic T-lymphocyte-associated antigen 4 (CTLA4) antibody (Ab) has been identified to stimulate Fc receptor-mediated active phagocytes in the tumor microenvironment, thereby generating “eat me” signals. This study postulates that concurrently targeting CD47 and CTLA4 could intensify the anti-tumor effects by simultaneously blocking the “don’t eat me” signal while triggering the “eat me” signal. The experimental data from this investigation confirm that the combined targeting of CD47 and CTLA4 enhances immunity against solid tumors in LLC cell-transplanted tumor-bearing mice. This effect is achieved by reducing myeloid-derived suppressor cell infiltration while increasing the presence of effector memory CD8+ T cells, NK1.1+ CD8+ T cells, and activated natural killer T cells. Meanwhile, combination therapy also alleviated anemia. Mechanistically, the anti-CD47 Ab is shown to upregulate CTLA4 levels in NSCLC cells by regulating Foxp1. Furthermore, targeting CD47 is demonstrated to promote tumor vascular normalization through the heightened infiltration of CD4+ T cells. These findings suggest that the dual targeting of CD47 and CTLA4 exerts anti-tumor effects by orchestrating the “eat me” and “don’t eat me” signals, reshaping the immune microenvironment, and fostering tumor vascular normalization. This combined therapeutic approach emerges as a potent strategy for effectively treating solid tumors.
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Howard, James P., Jenna L. Hutton, John M. Olson, and Gregory S. Payne. "Sla1p serves as the targeting signal recognition factor for NPFX(1,2)D-mediated endocytosis." Journal of Cell Biology 157, no. 2 (2002): 315–26. http://dx.doi.org/10.1083/jcb.200110027.

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Efficient endocytosis requires cytoplasmic domain targeting signals that specify incorporation of cargo into endocytic vesicles. Adaptor proteins play a central role in cargo collection by linking targeting signals to the endocytic machinery. We have characterized NPFX(1,2) (NPFX[1,2]D) targeting signals and identified the actin-associated protein Sla1p as the adaptor for NPFX(1,2)D-mediated endocytosis in Saccharomyces cerevisiae. 11 amino acids encompassing an NPFX(1,2)D sequence were sufficient to direct uptake of a truncated form of the pheromone receptor Ste2p. In this context, endocytic targeting activity was not sustained by conservative substitutions of the phenylalanine or aspartate. An NPFX1,2D-related sequence was identified in native Ste2p that functions redundantly with ubiquitin-based endocytic signals. A two-hybrid interaction screen for NPFX(1,2)D-interacting proteins yielded SLA1, but no genes encoding Eps15 homology (EH) domains, protein modules known to recognize NPF peptides. Furthermore, EH domains did not recognize an NPFX(1,2)D signal when directly tested by two-hybrid analysis. SLA1 disruption severely inhibited NPFX(1,2)D-mediated endocytosis, but only marginally affected ubiquitin-directed uptake. NPFX(1,2)D-dependent internalization required a conserved domain of Sla1p, SLA1 homology domain, which selectively bound an NPFX(1,2)D-containing fusion protein in vitro. Thus, through a novel NPF-binding domain, Sla1p serves as an endocytic targeting signal adaptor, providing a means to couple cargo with clathrin- and actin-based endocytic machineries.
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30

Jones, Jacob M., James C. Morrell, and Stephen J. Gould. "Multiple Distinct Targeting Signals in Integral Peroxisomal Membrane Proteins." Journal of Cell Biology 153, no. 6 (2001): 1141–50. http://dx.doi.org/10.1083/jcb.153.6.1141.

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Peroxisomal proteins are synthesized on free polysomes and then transported from the cytoplasm to peroxisomes. This process is mediated by two short well-defined targeting signals in peroxisomal matrix proteins, but a well-defined targeting signal has not yet been described for peroxisomal membrane proteins (PMPs). One assumption in virtually all prior studies of PMP targeting is that a given protein contains one, and only one, distinct targeting signal. Here, we show that the metabolite transporter PMP34, an integral PMP, contains at least two nonoverlapping sets of targeting information, either of which is sufficient for insertion into the peroxisome membrane. We also show that another integral PMP, the peroxin PEX13, also contains two independent sets of peroxisomal targeting information. These results challenge a major assumption of most PMP targeting studies. In addition, we demonstrate that PEX19, a factor required for peroxisomal membrane biogenesis, interacts with the two minimal targeting regions of PMP34. Together, these results raise the interesting possibility that PMP import may require novel mechanisms to ensure the solubility of integral PMPs before their insertion in the peroxisome membrane, and that PEX19 may play a central role in this process.
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31

Bode, A. M., and Z. Dong. "Targeting signal transduction pathways by chemopreventive agents." Mutation Research/Fundamental and Molecular Mechanisms of Mutagenesis 555, no. 1-2 (2004): 33–51. http://dx.doi.org/10.1016/j.mrfmmm.2004.05.018.

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32

Soendergaard, Christoffer, Fredrik Holmberg Bergenheim, Jakob Tveiten Bjerrum, and Ole Haagen Nielsen. "Targeting JAK-STAT signal transduction in IBD." Pharmacology & Therapeutics 192 (December 2018): 100–111. http://dx.doi.org/10.1016/j.pharmthera.2018.07.003.

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33

Auld, Douglas S., David Diller, and Koc-Kan Ho. "Targeting signal transduction with large combinatorial collections." Drug Discovery Today 7, no. 24 (2002): 1206–13. http://dx.doi.org/10.1016/s1359-6446(02)02530-8.

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34

Yeh, Jen Jen, and Channing J. Der. "Targeting signal transduction in pancreatic cancer treatment." Expert Opinion on Therapeutic Targets 11, no. 5 (2007): 673–94. http://dx.doi.org/10.1517/14728222.11.5.673.

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35

Ohnishi, Ken, and Takeo Ohnishi. "Hyperthermic sensitizers targeting heat-induced signal transductions." Annals of Cancer Research and Therapy 15, no. 2 (2007): 35–40. http://dx.doi.org/10.4993/acrt.15.35.

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36

Schliebs, Wolfgang, Jürgen Saidowsky, Bogos Agianian, Gabriele Dodt, Friedrich W. Herberg, and Wolf-H. Kunau. "Recombinant Human Peroxisomal Targeting Signal Receptor PEX5." Journal of Biological Chemistry 274, no. 9 (1999): 5666–73. http://dx.doi.org/10.1074/jbc.274.9.5666.

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37

Halleck, M. S., and M. Rechsteiner. "Antibody caging of a nuclear-targeting signal." Proceedings of the National Academy of Sciences 87, no. 19 (1990): 7551–54. http://dx.doi.org/10.1073/pnas.87.19.7551.

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38

Schleiff, E., and H. McBride. "The central matrix loop drives import of uncoupling protein 1 into mitochondria." Journal of Cell Science 113, no. 12 (2000): 2267–72. http://dx.doi.org/10.1242/jcs.113.12.2267.

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The uncoupling protein (UCP1) is a carrier protein of the inner mitochondrial membrane spanning the bilayer six times. It does not contain a typical amino-terminal targeting signal and the mechanism of targeting and insertion is unknown. Here we focus on the biogenesis of UCP1 by analysing the import signals contained within the three repeated units of the protein. The amino-terminal third of the protein can mediate insertion into the outer membrane and therefore acts as artificial targeting signal when fused to DHFR. However, in the context of full-length UCP, the targeting information contained within the first repeated unit is not sufficient to trigger insertion into the outer membrane. Deletion of either the first or third repeated unit from UCP1 did not reduce import into the inner membrane and bound to the outer membrane receptor protein hTom20 with the characteristics of full-length UCP1. Deletion of the second repeat of UCP1 completely abolished all import into the mitochondria. Consistent with this, the central repeat alone was efficiently imported to the inner membrane and bound hTom20 with the characteristics of UCP1. We conclude that the site for binding hTom20 is within the central repeat and that this domain contains the complete targeting signal for directing UCP1 to the inner membrane.
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39

Zhang, Yangyang, Minghua Liu, Jun Wang, et al. "Targeting Protein Kinase Inhibitors with Traditional Chinese Medicine." Current Drug Targets 20, no. 15 (2019): 1505–16. http://dx.doi.org/10.2174/1389450120666190802125959.

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Protein kinases play critical roles in the control of cell growth, proliferation, migration, and angiogenesis, through their catalytic activity. Over the past years, numerous protein kinase inhibitors have been identified and are being successfully used clinically. Traditional Chinese medicine (TCM) represents a large class of bioactive substances, and some of them display anticancer activity via inhibiting protein kinases signal pathway. Some of the TCM have been used to treat tumors clinically in China for many years. The p38mitogen-activated protein kinase (MAPK), phosphoinositide 3-kinase, serine/threonine-specific protein kinases (PI3K/AKT/mTOR), and extracellular signal-regulated kinases (ERK) pathways are considered important signals in cancer cell development. In the present article, the recent progress of TCM that exhibited significant inhibitory activity towards a range of protein kinases is discussed. The clinical efficacy of TCM with inhibitory effects on protein kinases in treating a tumor is also presented. The article also discussed the prospects and problems in the development of anticancer agents with TCM.
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40

DuBose, D. Ross, Samuel C. Wolff, Ai-Dong Qi, Izabela Naruszewicz, and Robert A. Nicholas. "Apical targeting of the P2Y4 receptor is directed by hydrophobic and basic residues in the cytoplasmic tail." American Journal of Physiology-Cell Physiology 304, no. 3 (2013): C228—C239. http://dx.doi.org/10.1152/ajpcell.00251.2012.

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The P2Y4 receptor is selectively targeted to the apical membrane in polarized epithelial cell lines and has been shown to play a key role in intestinal chloride secretion. In this study, we delimit a 23 amino acid sequence within the P2Y4 receptor C-tail that directs its apical targeting. Using a mutagenesis approach, we found that four hydrophobic residues near the COOH-terminal end of the signal are necessary for apical sorting, whereas two basic residues near the NH2-terminal end of the signal are involved to a lesser extent. Interestingly, mutation of the key hydrophobic residues results in a basolateral enrichment of the receptor construct, suggesting that the apical targeting sequence may prevent insertion or disrupt stability of the receptor at the basolateral membrane. The signal is not sequence specific, as an inversion of the 23 amino acid sequence does not disrupt apical targeting. We also show that the apical targeting sequence is an autonomous signal and is capable of redistributing the normally basolateral P2Y12 receptor, suggesting that the apical signal is dominant over the basolateral signal in the main body of the P2Y12 receptor. The targeting sequence is unique to the P2Y4 receptor, and sequence alignments of the COOH-terminal tail of mammalian orthologs reveal that the hydrophobic residues in the targeting signal are highly conserved. These data define the novel apical sorting signal of the P2Y4 receptor, which may represent a common mechanism for trafficking of epithelial transmembrane proteins.
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41

Hájek, P., J. Y. Koh, L. Jones, and D. M. Bedwell. "The amino terminus of the F1-ATPase beta-subunit precursor functions as an intramolecular chaperone to facilitate mitochondrial protein import." Molecular and Cellular Biology 17, no. 12 (1997): 7169–77. http://dx.doi.org/10.1128/mcb.17.12.7169.

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Mitochondrial import signals have been shown to function in many steps of mitochondrial protein import. Previous studies have shown that the F1-ATPase beta-subunit precursor (pre-F1beta) of the yeast Saccharomyces cerevisiae contains an extended, functionally redundant mitochondrial import signal at its amino terminus. However, the full significance of this functionally redundant targeting sequence has not been determined. We now report that the extended pre-F1beta signal acts to maintain the precursor in an import-competent conformation prior to import, in addition to its previously characterized roles in mitochondrial targeting and translocation. We found that this extended signal is required for the efficient posttranslational mitochondrial import of pre-F1beta both in vivo and in vitro. To determine whether the pre-F1beta signal directly influences precursor conformation, fusion proteins that contain wild-type and mutant forms of the pre-F1beta import signal attached to the model passenger protein dihydrofolate reductase (DHFR) were constructed. Deletions that reduced the import signal to a minimal functional unit decreased both the half-time of precursor folding and the efficiency of mitochondrial import. To confirm that the reduced mitochondrial import associated with this truncated signal was due to a defect in its ability to maintain DHFR in a loosely folded conformation, we introduced structurally destabilizing missense mutations into the DHFR passenger to block precursor folding independently of the import signal. We found that the truncated signal imported this destabilized form of DHFR as efficiently as the intact targeting signal, indicating that the primary defect associated with the minimal signal is an inability to maintain the precursor in a loosely folded conformation. Our results suggest that the loss of this intramolecular chaperone function leads to defects in the early stages of the import process.
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42

Blattner, J., B. Swinkels, H. Dörsam, T. Prospero, S. Subramani, and C. Clayton. "Glycosome assembly in trypanosomes: variations in the acceptable degeneracy of a COOH-terminal microbody targeting signal." Journal of Cell Biology 119, no. 5 (1992): 1129–36. http://dx.doi.org/10.1083/jcb.119.5.1129.

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Trypanosomes compartmentalize most of their glycolytic enzymes in a peroxisome-like microbody, the glycosome. The specificity of glycosomal targeting was examined by expression of chloramphenicol acetyltransferase fusion proteins in trypanosomes and monkey cells. Compartmentalization was assessed by cell fractionation, differential detergent permeabilization, and immunofluorescence. The targeting signal of trypanosome phosphoglycerate kinase resides in the COOH-terminal hexapeptide, NRWSSL; a basic amino acid is not required. The minimal targeting signal is, as for mammalian cells, a COOH-terminal tripeptide related to -SKL. However, the acceptable degeneracy of the signal for glycosomal targeting in trypanosomes is considerably greater than that for peroxisomal targeting in mammals, with particularly relaxed requirements in the penultimate position.
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43

Martoglio, B. "Intramembrane proteolysis and post-targeting functions of signal peptides." Biochemical Society Transactions 31, no. 6 (2003): 1243–47. http://dx.doi.org/10.1042/bst0311243.

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Signal sequences are the addresses of proteins destined for secretion. In eukaryotic cells, they mediate targeting to the endoplasmic reticulum membrane and insertion into the translocon. Thereafter, signal sequences are cleaved from the pre-protein and liberated into the endoplasmic reticulum membrane. We have recently reported that some liberated signal peptides are further processed by the intramembrane-cleaving aspartic protease signal peptide peptidase. Cleavage in the membrane-spanning portion of the signal peptide promotes the release of signal peptide fragments from the lipid bilayer. Typical processes that include intramembrane proteolysis is the regulatory or signalling function of cleavage products. Likewise, signal peptide fragments liberated upon intramembrane cleavage may promote such post-targeting functions in the cell.
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44

Grueneberg, D. A., K. J. Simon, K. Brennan, and M. Gilman. "Sequence-specific targeting of nuclear signal transduction pathways by homeodomain proteins." Molecular and Cellular Biology 15, no. 6 (1995): 3318–26. http://dx.doi.org/10.1128/mcb.15.6.3318.

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Cells translate extracellular signals into specific programs of gene expression that reflect their developmental history or identity. We present evidence that one way this interpretation may be performed is by cooperative interactions between serum response factor (SRF) and certain homeodomain proteins. We show that human and Drosophila homeodomain proteins of the paired class have the ability to recruit SRF to DNA sequences not efficiently recognized by SRF on its own, thereby imparting to a linked reporter gene the potential to respond to polypeptide growth factors. This activity requires both the DNA-binding activity of the homeodomain and putative protein-protein contact residues on the exposed surfaces of homeodomain helices 1 and 2. The ability of the homeodomain to impart signal responsiveness is DNA sequence specific, and this specificity differs from the simple DNA-binding specificity of the homeodomain in vitro. The homeodomain imparts response to a spectrum of signals characteristic of the natural SRF-binding site in the c-fos gene. Response to some of these signals is dependent on the secondary recruitment of SRF-dependent ternary complex factors, and we show directly that a homeodomain can promote the recruitment of one such factor, Elk1. We infer that SRF and homeodomains interact cooperatively on DNA and that formation of SRF-homeodomain complexes permits the recruitment of signal-responsive SRF accessory proteins. The ability to route extracellular signals to specific target genes is a novel activity of the homeodomain, which may contribute to the identity function displayed by many homeodomain genes.
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45

Wulfkuhle, J. D., I. E. Donina, N. H. Stark, et al. "Domain analysis of supervillin, an F-actin bundling plasma membrane protein with functional nuclear localization signals." Journal of Cell Science 112, no. 13 (1999): 2125–36. http://dx.doi.org/10.1242/jcs.112.13.2125.

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A growing number of actin-associated membrane proteins have been implicated in motile processes, adhesive interactions, and signal transduction to the cell nucleus. We report here that supervillin, an F-actin binding protein originally isolated from bovine neutrophil plasma membranes, contains functional nuclear targeting signals and localizes at or near vinculin-containing focal adhesion plaques in COS7-2 and CV1 cells. Overexpression of full-length supervillin in these cells disrupts the integrity of focal adhesion plaques and results in increased levels of F-actin and vinculin. Localization studies of chimeric proteins containing supervillin sequences fused with the enhanced green fluorescent protein indicate that: (1) the amino terminus promotes F-actin binding, targeting to focal adhesions, and limited nuclear localization; (2) the dominant nuclear targeting signal is in the center of the protein; and (3) the carboxy-terminal villin/gelsolin homology domain of supervillin does not, by itself, bind tightly to the actin cytoskeleton in vivo. Overexpression of chimeras containing both the amino-terminal F-actin binding site(s) and the dominant nuclear targeting signal results in the formation of large nuclear bundles containing F-actin, supervillin, and lamin. These results suggest that supervillin may contribute to cytoarchitecture in the nucleus, as well as at the plasma membrane.
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46

Spatola Rossi, Tatiana, and Verena Kriechbaumer. "An Interplay between Mitochondrial and ER Targeting of a Bacterial Signal Peptide in Plants." Plants 12, no. 3 (2023): 617. http://dx.doi.org/10.3390/plants12030617.

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Protein targeting is essential in eukaryotic cells to maintain cell function and organelle identity. Signal peptides are a major type of targeting sequences containing a tripartite structure, which is conserved across all domains in life. They are frequently included in recombinant protein design in plants to increase yields by directing them to the endoplasmic reticulum (ER) or apoplast. The processing of bacterial signal peptides by plant cells is not well understood but could aid in the design of efficient heterologous expression systems. Here we analysed the signal peptide of the enzyme PmoB from methanotrophic bacteria. In plant cells, the PmoB signal peptide targeted proteins to both mitochondria and the ER. This dual localisation was still observed in a mutated version of the signal peptide sequence with enhanced mitochondrial targeting efficiency. Mitochondrial targeting was shown to be dependent on a hydrophobic region involved in transport to the ER. We, therefore, suggest that the dual localisation could be due to an ER-SURF pathway recently characterised in yeast. This work thus sheds light on the processing of bacterial signal peptides by plant cells and proposes a novel pathway for mitochondrial targeting in plants.
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47

Addya, Sankar, Hindupur K. Anandatheerthavarada, Gopa Biswas, Shripad V. Bhagwat, Jayati Mullick, and Narayan G. Avadhani. "Targeting of NH2-terminal–processed Microsomal Protein to Mitochondria: A Novel Pathway for the Biogenesis of Hepatic Mitochondrial P450MT2." Journal of Cell Biology 139, no. 3 (1997): 589–99. http://dx.doi.org/10.1083/jcb.139.3.589.

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Cytochrome P4501A1 is a hepatic, microsomal membrane–bound enzyme that is highly induced by various xenobiotic agents. Two NH2-terminal truncated forms of this P450, termed P450MT2a and MT2b, are also found localized in mitochondria from β-naphthoflavone–induced livers. In this paper, we demonstrate that P4501A1 has a chimeric NH2-terminal signal that facilitates the targeting of the protein to both the ER and mitochondria. The NH2-terminal 30–amino acid stretch of P4501A1 is thought to provide signals for ER membrane insertion and also stop transfer. The present study provides evidence that a sequence motif immediately COOH-terminal (residues 33–44) to the transmembrane domain functions as a mitochondrial targeting signal under both in vivo and in vitro conditions, and that the positively charged residues at positions 34 and 39 are critical for mitochondrial targeting. Results suggest that 25% of P4501A1 nascent chains, which escape ER membrane insertion, are processed by a liver cytosolic endoprotease. We postulate that the NH2-terminal proteolytic cleavage activates a cryptic mitochondrial targeting signal. Immunofluorescence microscopy showed that a portion of transiently expressed P4501A1 is colocalized with the mitochondrial-specific marker protein cytochrome oxidase subunit I. The mitochondrial-associated MT2a and MT2b are localized within the inner membrane compartment, as tested by resistance to limited proteolysis in both intact mitochondria and mitoplasts. Our results therefore describe a novel mechanism whereby proteins with chimeric signal sequence are targeted to the ER as well as to the mitochondria.
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48

Goping, Ing Swie, Atan Gross, Josée N. Lavoie, et al. "Regulated Targeting of BAX to Mitochondria." Journal of Cell Biology 143, no. 1 (1998): 207–15. http://dx.doi.org/10.1083/jcb.143.1.207.

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The proapoptotic protein BAX contains a single predicted transmembrane domain at its COOH terminus. In unstimulated cells, BAX is located in the cytosol and in peripheral association with intracellular membranes including mitochondria, but inserts into mitochondrial membranes after a death signal. This failure to insert into mitochondrial membrane in the absence of a death signal correlates with repression of the transmembrane signal-anchor function of BAX by the NH2-terminal domain. Targeting can be instated by deleting the domain or by replacing the BAX transmembrane segment with that of BCL-2. In stimulated cells, the contribution of the NH2 terminus of BAX correlates with further exposure of this domain after membrane insertion of the protein. The peptidyl caspase inhibitor zVAD-fmk partly blocks the stimulated mitochondrial membrane insertion of BAX in vivo, which is consistent with the ability of apoptotic cell extracts to support mitochondrial targeting of BAX in vitro, dependent on activation of caspase(s). Taken together, our results suggest that regulated targeting of BAX to mitochondria in response to a death signal is mediated by discrete domains within the BAX polypeptide. The contribution of one or more caspases may reflect an initiation and/or amplification of this regulated targeting.
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49

Hamilton, VaNae, Ujjal K. Singha, Joseph T. Smith, Ebony Weems, and Minu Chaudhuri. "Trypanosome Alternative Oxidase Possesses both an N-Terminal and Internal Mitochondrial Targeting Signal." Eukaryotic Cell 13, no. 4 (2014): 539–47. http://dx.doi.org/10.1128/ec.00312-13.

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ABSTRACTRecognition of mitochondrial targeting signals (MTS) by receptor translocases of outer and inner membranes of mitochondria is one of the prerequisites for import of nucleus-encoded proteins into this organelle. The MTS for a majority of trypanosomatid mitochondrial proteins have not been well defined. Here we analyzed the targeting signal for trypanosome alternative oxidase (TAO), which functions as the sole terminal oxidase in the infective form ofTrypanosoma brucei. Deleting the first 10 of 24 amino acids predicted to be the classical N-terminal MTS of TAO did not affect its import into mitochondriain vitro. Furthermore, ectopically expressed TAO was targeted to mitochondria in both forms of the parasite even after deletion of first 40 amino acid residues. However, deletion of more than 20 amino acid residues from the N terminus reduced the efficiency of import. These data suggest that besides an N-terminal MTS, TAO possesses an internal mitochondrial targeting signal. In addition, both the N-terminal MTS and the mature TAO protein were able to target a cytosolic protein, dihydrofolate reductase (DHFR), to aT. bruceimitochondrion. Further analysis identified a cryptic internal MTS of TAO, located within amino acid residues 115 to 146, which was fully capable of targeting DHFR to mitochondria. The internal signal was more efficient than the N-terminal MTS for import of this heterologous protein. Together, these results show that TAO possesses a cleavable N-terminal MTS as well as an internal MTS and that these signals act together for efficient import of TAO into mitochondria.
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50

Wild, Klemens, Matthias M. M. Becker, Georg Kempf, and Irmgard Sinning. "Structure, dynamics and interactions of large SRP variants." Biological Chemistry 401, no. 1 (2019): 63–80. http://dx.doi.org/10.1515/hsz-2019-0282.

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Abstract Co-translational protein targeting to membranes relies on the signal recognition particle (SRP) system consisting of a cytosolic ribonucleoprotein complex and its membrane-associated receptor. SRP recognizes N-terminal cleavable signals or signal anchor sequences, retards translation, and delivers ribosome-nascent chain complexes (RNCs) to vacant translocation channels in the target membrane. While our mechanistic understanding is well advanced for the small bacterial systems it lags behind for the large bacterial, archaeal and eukaryotic SRP variants including an Alu and an S domain. Here we describe recent advances on structural and functional insights in domain architecture, particle dynamics and interplay with RNCs and translocon and GTP-dependent regulation of co-translational protein targeting stimulated by SRP RNA.
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