5dfz

Structural highlights

Function

[VPS38_YEAST] Involved in endosome-to-Golgi retrograde transport as part of the VPS34 PI3-kinase complex II. This complex is required for the endosome-to-Golgi retrieval of PEP1 and KEX2, and the recruitment of VPS5 and VPS7, two components of the retromer complex, to endosomal membranes (probably through generating a specific pool of phosphatidylinositol 3-phosphate allowing the recruitment of the retromer complex proteins to the endosome). Mediates the interaction between VPS30 and the VPS34-VPS15 core complex, leading to the recruitment of VPS30 to the membrane.^{[1] [2] [3]} [VPS15_YEAST] Serine/threonine-protein kinase required for cytoplasm to vacuole transport (Cvt) and autophagy as a part of the autophagy-specific VPS34 PI3-kinase complex I. This complex is essential to recruit the ATG8-phosphatidylinositol conjugate and the ATG12-ATG5 conjugate to the pre-autophagosomal structure. Is also involved in endosome-to-Golgi retrograde transport as part of the VPS34 PI3-kinase complex II. This second complex is required for the endosome-to-Golgi retrieval of PEP1 and KEX2, and the recruitment of VPS5 and VPS7, two components of the retromer complex, to endosomal membranes (probably through the synthesis of a specific pool of phosphatidylinositol 3-phosphate recruiting the retromer to the endosomes). By regulating VPS34 kinase activity, VPS15 appears to be essential for the efficient delivery of soluble hydrolases to the yeast vacuole.^{[4] [5] [6] [7] [8] [9] [10] [11] [12]} [VPS34_YEAST] Phosphatidylinositol 3-kinase required for cytoplasm to vacuole transport (Cvt) and autophagy as a part of the autophagy-specific VPS34 PI3-kinase complex I. This complex is essential to recruit the ATG8-phosphatidylinositol conjugate and the ATG12-ATG5 conjugate to the pre-autophagosomal structure. Also involved in endosome-to-Golgi retrograde transport as part of the VPS34 PI3-kinase complex II. This second complex is required for the endosome-to-Golgi retrieval of PEP1 and KEX2, and the recruitment of VPS5 and VPS7, two components of the retromer complex, to endosomal membranes (probably through the synthesis of a specific pool of phosphatidylinositol 3-phosphate recruiting the retromer to the endosomes). Its activation by VPS15 may lead to the phosphorylation of phosphatidylinositol in the sorting compartment membrane. Finally, it might also be involved in ethanol tolerance and cell wall integrity.^{[13] [14] [15] [16] [17] [18] [19] [20] [21] [22]} [BECN1_YEAST] Required for cytoplasm to vacuole transport (Cvt), autophagy, nucleophagy, and mitophagy, as a part of the autophagy-specific VPS34 PI3-kinase complex I. This complex is essential to recruit the ATG8-phosphatidylinositol conjugate and the ATG12-ATG5 conjugate to the pre-autophagosomal structure. Also involved in endosome-to-Golgi retrograde transport as part of the VPS34 PI3-kinase complex II. This second complex is required for the endosome-to-Golgi retrieval of PEP1 and KEX2, and the recruitment of VPS5 and VPS7, two components of the retromer complex, to endosomal membranes (probably through the synthesis of a specific pool of phosphatidylinositol 3-phosphate recruiting the retromer to the endosomes). Plays also a role in regulation of filamentous growth.^{[23] [24] [25] [26] [27] [28] [29] [30] [31] [32] [33] [34] [35] [36]}

References

1. ↑ Kihara A, Noda T, Ishihara N, Ohsumi Y. Two distinct Vps34 phosphatidylinositol 3-kinase complexes function in autophagy and carboxypeptidase Y sorting in Saccharomyces cerevisiae. J Cell Biol. 2001 Feb 5;152(3):519-30. PMID:11157979
2. ↑ Burda P, Padilla SM, Sarkar S, Emr SD. Retromer function in endosome-to-Golgi retrograde transport is regulated by the yeast Vps34 PtdIns 3-kinase. J Cell Sci. 2002 Oct 15;115(Pt 20):3889-900. PMID:12244127
3. ↑ Luo W, Chang A. Novel genes involved in endosomal traffic in yeast revealed by suppression of a targeting-defective plasma membrane ATPase mutant. J Cell Biol. 1997 Aug 25;138(4):731-46. PMID:9265642
4. ↑ Herman PK, Stack JH, DeModena JA, Emr SD. A novel protein kinase homolog essential for protein sorting to the yeast lysosome-like vacuole. Cell. 1991 Jan 25;64(2):425-37. PMID:1988155
5. ↑ Robinson JS, Klionsky DJ, Banta LM, Emr SD. Protein sorting in Saccharomyces cerevisiae: isolation of mutants defective in the delivery and processing of multiple vacuolar hydrolases. Mol Cell Biol. 1988 Nov;8(11):4936-48. PMID:3062374
6. ↑ Herman PK, Stack JH, Emr SD. A genetic and structural analysis of the yeast Vps15 protein kinase: evidence for a direct role of Vps15p in vacuolar protein delivery. EMBO J. 1991 Dec;10(13):4049-60. PMID:1756716
7. ↑ Stack JH, Herman PK, Schu PV, Emr SD. A membrane-associated complex containing the Vps15 protein kinase and the Vps34 PI 3-kinase is essential for protein sorting to the yeast lysosome-like vacuole. EMBO J. 1993 May;12(5):2195-204. PMID:8387919
8. ↑ Vida TA, Huyer G, Emr SD. Yeast vacuolar proenzymes are sorted in the late Golgi complex and transported to the vacuole via a prevacuolar endosome-like compartment. J Cell Biol. 1993 Jun;121(6):1245-56. PMID:8509446
9. ↑ Stack JH, Emr SD. Vps34p required for yeast vacuolar protein sorting is a multiple specificity kinase that exhibits both protein kinase and phosphatidylinositol-specific PI 3-kinase activities. J Biol Chem. 1994 Dec 16;269(50):31552-62. PMID:7989323
10. ↑ Nothwehr SF, Bryant NJ, Stevens TH. The newly identified yeast GRD genes are required for retention of late-Golgi membrane proteins. Mol Cell Biol. 1996 Jun;16(6):2700-7. PMID:8649377
11. ↑ Kihara A, Noda T, Ishihara N, Ohsumi Y. Two distinct Vps34 phosphatidylinositol 3-kinase complexes function in autophagy and carboxypeptidase Y sorting in Saccharomyces cerevisiae. J Cell Biol. 2001 Feb 5;152(3):519-30. PMID:11157979
12. ↑ Burda P, Padilla SM, Sarkar S, Emr SD. Retromer function in endosome-to-Golgi retrograde transport is regulated by the yeast Vps34 PtdIns 3-kinase. J Cell Sci. 2002 Oct 15;115(Pt 20):3889-900. PMID:12244127
13. ↑ Kihara A, Noda T, Ishihara N, Ohsumi Y. Two distinct Vps34 phosphatidylinositol 3-kinase complexes function in autophagy and carboxypeptidase Y sorting in Saccharomyces cerevisiae. J Cell Biol. 2001 Feb 5;152(3):519-30. PMID:11157979
14. ↑ Takahashi T, Shimoi H, Ito K. Identification of genes required for growth under ethanol stress using transposon mutagenesis in Saccharomyces cerevisiae. Mol Genet Genomics. 2001 Aug;265(6):1112-9. PMID:11523784
15. ↑ Burda P, Padilla SM, Sarkar S, Emr SD. Retromer function in endosome-to-Golgi retrograde transport is regulated by the yeast Vps34 PtdIns 3-kinase. J Cell Sci. 2002 Oct 15;115(Pt 20):3889-900. PMID:12244127
16. ↑ Herman PK, Emr SD. Characterization of VPS34, a gene required for vacuolar protein sorting and vacuole segregation in Saccharomyces cerevisiae. Mol Cell Biol. 1990 Dec;10(12):6742-54. PMID:2247081
17. ↑ Auger KR, Carpenter CL, Cantley LC, Varticovski L. Phosphatidylinositol 3-kinase and its novel product, phosphatidylinositol 3-phosphate, are present in Saccharomyces cerevisiae. J Biol Chem. 1989 Dec 5;264(34):20181-4. PMID:2555343
18. ↑ Robinson JS, Klionsky DJ, Banta LM, Emr SD. Protein sorting in Saccharomyces cerevisiae: isolation of mutants defective in the delivery and processing of multiple vacuolar hydrolases. Mol Cell Biol. 1988 Nov;8(11):4936-48. PMID:3062374
19. ↑ Munn AL, Riezman H. Endocytosis is required for the growth of vacuolar H(+)-ATPase-defective yeast: identification of six new END genes. J Cell Biol. 1994 Oct;127(2):373-86. PMID:7929582
20. ↑ Stack JH, Emr SD. Vps34p required for yeast vacuolar protein sorting is a multiple specificity kinase that exhibits both protein kinase and phosphatidylinositol-specific PI 3-kinase activities. J Biol Chem. 1994 Dec 16;269(50):31552-62. PMID:7989323
21. ↑ Schu PV, Takegawa K, Fry MJ, Stack JH, Waterfield MD, Emr SD. Phosphatidylinositol 3-kinase encoded by yeast VPS34 gene essential for protein sorting. Science. 1993 Apr 2;260(5104):88-91. PMID:8385367
22. ↑ Stack JH, Herman PK, Schu PV, Emr SD. A membrane-associated complex containing the Vps15 protein kinase and the Vps34 PI 3-kinase is essential for protein sorting to the yeast lysosome-like vacuole. EMBO J. 1993 May;12(5):2195-204. PMID:8387919
23. ↑ Kihara A, Noda T, Ishihara N, Ohsumi Y. Two distinct Vps34 phosphatidylinositol 3-kinase complexes function in autophagy and carboxypeptidase Y sorting in Saccharomyces cerevisiae. J Cell Biol. 2001 Feb 5;152(3):519-30. PMID:11157979
24. ↑ Suzuki K, Kirisako T, Kamada Y, Mizushima N, Noda T, Ohsumi Y. The pre-autophagosomal structure organized by concerted functions of APG genes is essential for autophagosome formation. EMBO J. 2001 Nov 1;20(21):5971-81. PMID:11689437 doi:10.1093/emboj/20.21.5971
25. ↑ Burda P, Padilla SM, Sarkar S, Emr SD. Retromer function in endosome-to-Golgi retrograde transport is regulated by the yeast Vps34 PtdIns 3-kinase. J Cell Sci. 2002 Oct 15;115(Pt 20):3889-900. PMID:12244127
26. ↑ Kruse KB, Brodsky JL, McCracken AA. Characterization of an ERAD gene as VPS30/ATG6 reveals two alternative and functionally distinct protein quality control pathways: one for soluble Z variant of human alpha-1 proteinase inhibitor (A1PiZ) and another for aggregates of A1PiZ. Mol Biol Cell. 2006 Jan;17(1):203-12. Epub 2005 Nov 2. PMID:16267277 doi:http://dx.doi.org/10.1091/mbc.E04-09-0779
27. ↑ Zhang Y, Qi H, Taylor R, Xu W, Liu LF, Jin S. The role of autophagy in mitochondria maintenance: characterization of mitochondrial functions in autophagy-deficient S. cerevisiae strains. Autophagy. 2007 Jul-Aug;3(4):337-46. Epub 2007 Jul 9. PMID:17404498
28. ↑ Ma J, Jin R, Dobry CJ, Lawson SK, Kumar A. Overexpression of autophagy-related genes inhibits yeast filamentous growth. Autophagy. 2007 Nov-Dec;3(6):604-9. Epub 2007 Jul 24. PMID:17700056
29. ↑ Hirayama H, Fujita M, Yoko-o T, Jigami Y. O-mannosylation is required for degradation of the endoplasmic reticulum-associated degradation substrate Gas1*p via the ubiquitin/proteasome pathway in Saccharomyces cerevisiae. J Biochem. 2008 Apr;143(4):555-67. doi: 10.1093/jb/mvm249. Epub 2008 Jan 7. PMID:18182384 doi:http://dx.doi.org/10.1093/jb/mvm249
30. ↑ Krick R, Muehe Y, Prick T, Bremer S, Schlotterhose P, Eskelinen EL, Millen J, Goldfarb DS, Thumm M. Piecemeal microautophagy of the nucleus requires the core macroautophagy genes. Mol Biol Cell. 2008 Oct;19(10):4492-505. doi: 10.1091/mbc.E08-04-0363. Epub 2008 , Aug 13. PMID:18701704 doi:http://dx.doi.org/10.1091/mbc.E08-04-0363
31. ↑ Fu L, Sztul E. ER-associated complexes (ERACs) containing aggregated cystic fibrosis transmembrane conductance regulator (CFTR) are degraded by autophagy. Eur J Cell Biol. 2009 Apr;88(4):215-26. doi: 10.1016/j.ejcb.2008.11.003. Epub, 2009 Jan 7. PMID:19131141 doi:http://dx.doi.org/10.1016/j.ejcb.2008.11.003
32. ↑ Noda NN, Kobayashi T, Adachi W, Fujioka Y, Ohsumi Y, Inagaki F. Structure of the novel C-terminal domain of vacuolar protein sorting 30/autophagy-related protein 6 and its specific role in autophagy. J Biol Chem. 2012 May 11;287(20):16256-66. doi: 10.1074/jbc.M112.348250. Epub, 2012 Mar 21. PMID:22437838 doi:http://dx.doi.org/10.1074/jbc.M112.348250
33. ↑ Fogel AI, Dlouhy BJ, Wang C, Ryu SW, Neutzner A, Hasson SA, Sideris DP, Abeliovich H, Youle RJ. Role of membrane association and Atg14-dependent phosphorylation in beclin-1-mediated autophagy. Mol Cell Biol. 2013 Sep;33(18):3675-88. doi: 10.1128/MCB.00079-13. Epub 2013 Jul , 22. PMID:23878393 doi:http://dx.doi.org/10.1128/MCB.00079-13
34. ↑ Tsukada M, Ohsumi Y. Isolation and characterization of autophagy-defective mutants of Saccharomyces cerevisiae. FEBS Lett. 1993 Oct 25;333(1-2):169-74. PMID:8224160
35. ↑ Seaman MN, Marcusson EG, Cereghino JL, Emr SD. Endosome to Golgi retrieval of the vacuolar protein sorting receptor, Vps10p, requires the function of the VPS29, VPS30, and VPS35 gene products. J Cell Biol. 1997 Apr 7;137(1):79-92. PMID:9105038
36. ↑ Kametaka S, Okano T, Ohsumi M, Ohsumi Y. Apg14p and Apg6/Vps30p form a protein complex essential for autophagy in the yeast, Saccharomyces cerevisiae. J Biol Chem. 1998 Aug 28;273(35):22284-91. PMID:9712845
37. ↑ Rostislavleva K, Soler N, Ohashi Y, Zhang L, Pardon E, Burke JE, Masson GR, Johnson C, Steyaert J, Ktistakis NT, Williams RL. Structure and flexibility of the endosomal Vps34 complex reveals the basis of its function on membranes. Science. 2015 Oct 9;350(6257):aac7365. doi: 10.1126/science.aac7365. PMID:26450213 doi:http://dx.doi.org/10.1126/science.aac7365