VPS35

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Vacuolar protein sorting-associated protein 35 is a protein that in humans is encoded by the VPS35 gene.[1][2]

This gene belongs to a group of vacuolar protein sorting (VPS) genes. The encoded protein is a component of a large multimeric complex, termed the retromer complex, involved in retrograde transport of proteins from endosomes to the trans-Golgi network. The close structural similarity between the yeast and human proteins that make up this complex suggests a similarity in function. Expression studies in yeast and mammalian cells indicate that this protein interacts directly with VPS35, which serves as the core of the retromer complex.[2]

Structure

Vps35 is the largest subunit of retromer with the molecular weight of 92-kDa and functions as the central platform for the assembly of Vps26 and Vps29.[3] Vps35 resembles many other helical solenoid proteins including AP adaptor protein complexes that are characterized with repeated structural units in a continuous superhelix arrangement involved in coated vesicle trafficking. The curved surface of the 6 even-numbered helices within solenoid structure with series of ridges separating hydrophobic grooves function as potential cargo binding sites.[4] The C-terminal of Vps35 contains an α-solenoid fold that fits into the metal binding pocket of Vps29.[5]

A conserved PRLYL motif at the N-terminus of Vps35 is involved in the binding of Vps26.[6][7] The structural binding motifs enable this subunit to act as a linker between the SNX dimers and Vps trimer complex, and the binding sites targeting to the N-terminal region of SNX subunits are located at the both ends of the trimer. A study has shown that the knockdown of Vps35 in human HEp-2 epithelial cells had defect on the endosomal recycling of transferrin by DMT1 due to the mis-sorting of DMT1-II to the lysosomal membrane associated protein (LAMP2) structures.[8]

References

  1. Zhang P, Yu L, Gao J, Fu Q, Dai F, Zhao Y, Zheng L, Zhao S (Jan 2001). "Cloning and characterization of human VPS35 and mouse Vps35 and mapping of VPS35 to human chromosome 16q13-q21". Genomics. 70 (2): 253–7. doi:10.1006/geno.2000.6380. PMID 11112353.
  2. 2.0 2.1 "Entrez Gene: VPS35 vacuolar protein sorting 35 homolog (S. cerevisiae)".
  3. Hierro A, Rojas AL, Rojas R, Murthy N, Effantin G, Kajava AV, Steven AC, Bonifacino JS, Hurley JH (October 2007). "Functional architecture of the retromer cargo-recognition complex". Nature. 449 (7165): 1063–7. doi:10.1038/nature06216. PMC 2377034. PMID 17891154.
  4. Nothwehr SF, Bruinsma P, Strawn LA (April 1999). "Distinct domains within Vps35p mediate the retrieval of two different cargo proteins from the yeast prevacuolar/endosomal compartment". Mol. Biol. Cell. 10 (4): 875–90. doi:10.1091/mbc.10.4.875. PMC 25208. PMID 10198044.
  5. Collins BM, Skinner CF, Watson PJ, Seaman MN, Owen DJ (July 2005). "Vps29 has a phosphoesterase fold that acts as a protein interaction scaffold for retromer assembly". Nat. Struct. Mol. Biol. 12 (7): 594–602. doi:10.1038/nsmb954. PMID 15965486.
  6. Reddy JV, Seaman MN (October 2001). "Vps26p, a component of retromer, directs the interactions of Vps35p in endosome-to-Golgi retrieval". Mol. Biol. Cell. 12 (10): 3242–56. doi:10.1091/mbc.12.10.3242. PMC 60170. PMID 11598206.
  7. Zhao X, Nothwehr S, Lara-Lemus R, Zhang BY, Peter H, Arvan P (December 2007). "Dominant-negative behavior of mammalian Vps35 in yeast requires a conserved PRLYL motif involved in retromer assembly". Traffic. 8 (12): 1829–40. doi:10.1111/j.1600-0854.2007.00658.x. PMC 2532708. PMID 17916227.
  8. Tabuchi M, Yanatori I, Kawai Y, Kishi F (March 2010). "Retromer-mediated direct sorting is required for proper endosomal recycling of the mammalian iron transporter DMT1". J. Cell Sci. 123 (Pt 5): 756–66. doi:10.1242/jcs.060574. PMID 20164305.

Further reading



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