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Gene Review

PEP1  -  Pep1p

Saccharomyces cerevisiae S288c

Synonyms: CPY receptor, Carboxypeptidase Y receptor, Carboxypeptidase Y-deficient protein 1, Sortilin VPS10, VPS10, ...
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High impact information on PEP1

  • Mutations in VPS10 result in the selective missorting and secretion of CPY; all other vacuolar proteins tested are delivered to the vacuole in vps10 mutants [1].
  • The S. cerevisiae VPS10 (vacuolar protein sorting) gene encodes a type I transmembrane protein of 1577 amino acids required for the sorting of the soluble vacuolar protein carboxypeptidase Y (CPY) [1].
  • Analogous to the mannose-6-phosphate receptors in mammalian cells, the VPS10 gene encodes a transmembrane sorting receptor for the yeast vacuolar hydrolase carboxypeptidase Y [2].
  • Disruption of KEX2, which blocks intracellular processing to insulin, quantitatively reroutes ICFP to the cell surface, whereas loss of the Vps10p sorting receptor is without effect [3].
  • Furthermore, mutations in the cytosolic domains of A-ALP and another cargo protein, Vps10p, were identified that suppressed cargo-specific mutations in Vps35p but did not suppress the retrieval defects of a vps35 null mutation [4].

Biological context of PEP1

  • This phenotype is similar to that seen in cells with mutations in the previously characterized VPS10 and VPS35 genes [5].
  • Information sufficient for vacuolar sorting of the normally secreted protein invertase has in fusion constructs previously been found to reside in the propeptide of proteinase A. We found that sorting of such a hybrid protein is dependent on the vacuolar protein-sorting receptor Vps10p [6].
  • An 11.4 kb DNA segment on the left arm of yeast chromosome II carries the carboxypeptidase Y sorting gene PEP1, as well as ACH1, FUS3 and a putative ARS [7].
  • Competition with a putative MADS box consensus binding site from the promoter of the coordinately regulated opaque-phase-specific gene PEP1 (SAP1) and the human MADS box consensus binding site for serum response factor demonstrated that one of the three complexes formed was specific to the OP4 sequence [8].

Anatomical context of PEP1


Associations of PEP1 with chemical compounds

  • A tyrosine-based signal (YSSL80) within the cytosolic domain enables Vps10p to cycle between the late-Golgi and prevacuolar/endosomal compartments [12].
  • A chimeric receptor was constructed by substituting the cytoplasmic domain of M(r) 300,000 mannose 6-phosphate receptor with the Vps10p cytoplasmic tail [13].
  • Growth inhibition of pmr1 mutants on Ca2+-deficient media is overcome by expression of other Ca2+ pumps, including a SERCA-type Ca2+ adenosine triphosphatase from rabbit, or by Vps10, a sorting receptor guiding non-native luminal proteins to the vacuole [14].

Physical interactions of PEP1

  • Vps35p recognizes cargo molecules such as Vps10p and interacts strongly with Vps29p [15].
  • On the basis of these and other observations, we propose that the Vps17p protein complex may participate in the intracellular trafficking of the Vps10p-sorting receptor, as well as other later-Golgi proteins [16].
  • Moreover, the cytoplasmic tail of the Vps10p was found to interact with GGA1 and GGA2, two mammalian members of a recently discovered family of clathrin-binding cytosolic proteins that participate in trans-Golgi network-endosome trafficking in both mammals and yeast [13].
  • Vps35p is required for the prevacuolar compartment-to-TGN transport of both A-ALP and Vps10p [17].

Other interactions of PEP1

  • A temperature conditional allele of the VPS35 gene was generated and has been found to cause missorting/secretion of CPY and also Vps10p to mislocalize to a vacuolar membrane fraction at the nonpermissive temperature [5].
  • Interestingly, overexpression of two telomere-linked VPS10 homologues, VTH1 and VTH2 suppressed the missorting phenotypes of a deltavps10 strain [6].
  • This was unexpected, as strains disrupted for VPS10 sort more than 85% of the proteinase A to the vacuole [6].
  • The latter defect is apparently due to an inability to localize the carboxypeptidase Y sorting receptor, Vps10p, to the Golgi since it is rapidly degraded in the vacuole in vps5 mutants [18].
  • As was observed with the late Golgi protein Kex2p, Vps10p is unstable in a vps1 mutant [19].

Analytical, diagnostic and therapeutic context of PEP1

  • Immunofluorescence studies localizing the proteins ALP, Kex2 (a TGN resident protein), and Vps10 (the CPY receptor for transport from the TGN to the vacuole) suggest that inadequate function of this ArfGAP pair leads to a fragmentation of TGN, with effects on secretion and endosomal transport [20].


  1. The sorting receptor for yeast vacuolar carboxypeptidase Y is encoded by the VPS10 gene. Marcusson, E.G., Horazdovsky, B.F., Cereghino, J.L., Gharakhanian, E., Emr, S.D. Cell (1994) [Pubmed]
  2. Receptor-mediated protein sorting to the vacuole in yeast: roles for a protein kinase, a lipid kinase and GTP-binding proteins. Stack, J.H., Horazdovsky, B., Emr, S.D. Annu. Rev. Cell Dev. Biol. (1995) [Pubmed]
  3. Intracellular retention of newly synthesized insulin in yeast is caused by endoproteolytic processing in the Golgi complex. Zhang , B., Chang, A., Kjeldsen, T.B., Arvan, P. J. Cell Biol. (2001) [Pubmed]
  4. Sorting of yeast membrane proteins into an endosome-to-Golgi pathway involves direct interaction of their cytosolic domains with Vps35p. Nothwehr, S.F., Ha, S.A., Bruinsma, P. J. Cell Biol. (2000) [Pubmed]
  5. Endosome to Golgi retrieval of the vacuolar protein sorting receptor, Vps10p, requires the function of the VPS29, VPS30, and VPS35 gene products. Seaman, M.N., Marcusson, E.G., Cereghino, J.L., Emr, S.D. J. Cell Biol. (1997) [Pubmed]
  6. Multiple pathways for vacuolar sorting of yeast proteinase A. Westphal, V., Marcusson, E.G., Winther, J.R., Emr, S.D., van den Hazel, H.B. J. Biol. Chem. (1996) [Pubmed]
  7. An 11.4 kb DNA segment on the left arm of yeast chromosome II carries the carboxypeptidase Y sorting gene PEP1, as well as ACH1, FUS3 and a putative ARS. Van Dyck, L., Purnelle, B., Skala, J., Goffeau, A. Yeast (1992) [Pubmed]
  8. A MADS box protein consensus binding site is necessary and sufficient for activation of the opaque-phase-specific gene OP4 of Candida albicans. Lockhart, S.R., Nguyen, M., Srikantha, T., Soll, D.R. J. Bacteriol. (1998) [Pubmed]
  9. VPS27 controls vacuolar and endocytic traffic through a prevacuolar compartment in Saccharomyces cerevisiae. Piper, R.C., Cooper, A.A., Yang, H., Stevens, T.H. J. Cell Biol. (1995) [Pubmed]
  10. Vps10p cycles between the TGN and the late endosome via the plasma membrane in clathrin mutants. Deloche, O., Schekman, R.W. Mol. Biol. Cell (2002) [Pubmed]
  11. Vps10p transport from the trans-Golgi network to the endosome is mediated by clathrin-coated vesicles. Deloche, O., Yeung, B.G., Payne, G.S., Schekman, R. Mol. Biol. Cell (2001) [Pubmed]
  12. Vps10p cycles between the late-Golgi and prevacuolar compartments in its function as the sorting receptor for multiple yeast vacuolar hydrolases. Cooper, A.A., Stevens, T.H. J. Cell Biol. (1996) [Pubmed]
  13. The yeast Vps10p cytoplasmic tail mediates lysosomal sorting in mammalian cells and interacts with human GGAs. Dennes, A., Madsen, P., Nielsen, M.S., Petersen, C.M., Pohlmann, R. J. Biol. Chem. (2002) [Pubmed]
  14. The medial-Golgi ion pump Pmr1 supplies the yeast secretory pathway with Ca2+ and Mn2+ required for glycosylation, sorting, and endoplasmic reticulum-associated protein degradation. Dürr, G., Strayle, J., Plemper, R., Elbs, S., Klee, S.K., Catty, P., Wolf, D.H., Rudolph, H.K. Mol. Biol. Cell (1998) [Pubmed]
  15. Vps26p, a component of retromer, directs the interactions of Vps35p in endosome-to-Golgi retrieval. Reddy, J.V., Seaman, M.N. Mol. Biol. Cell (2001) [Pubmed]
  16. A sorting nexin-1 homologue, Vps5p, forms a complex with Vps17p and is required for recycling the vacuolar protein-sorting receptor. Horazdovsky, B.F., Davies, B.A., Seaman, M.N., McLaughlin, S.A., Yoon, S., Emr, S.D. Mol. Biol. Cell (1997) [Pubmed]
  17. Distinct domains within Vps35p mediate the retrieval of two different cargo proteins from the yeast prevacuolar/endosomal compartment. Nothwehr, S.F., Bruinsma, P., Strawn, L.A. Mol. Biol. Cell (1999) [Pubmed]
  18. The yeast VPS5/GRD2 gene encodes a sorting nexin-1-like protein required for localizing membrane proteins to the late Golgi. Nothwehr, S.F., Hindes, A.E. J. Cell. Sci. (1997) [Pubmed]
  19. The cytoplasmic tail domain of the vacuolar protein sorting receptor Vps10p and a subset of VPS gene products regulate receptor stability, function, and localization. Cereghino, J.L., Marcusson, E.G., Emr, S.D. Mol. Biol. Cell (1995) [Pubmed]
  20. The Gcs1 and Age2 ArfGAP proteins provide overlapping essential function for transport from the yeast trans-Golgi network. Poon, P.P., Nothwehr, S.F., Singer, R.A., Johnston, G.C. J. Cell Biol. (2001) [Pubmed]
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