VPS26A

{{Short description|Protein-coding gene in the species Homo sapiens}}

Vacuolar protein sorting-associated protein 26A is a protein that in humans is encoded by the VPS26A gene.{{cite journal | vauthors = Lee JJ, Radice G, Perkins CP, Costantini F | title = Identification and characterization of a novel, evolutionarily conserved gene disrupted by the murine H beta 58 embryonic lethal transgene insertion | journal = Development | volume = 115 | issue = 1 | pages = 277–88 |date=Aug 1992 | doi = 10.1242/dev.115.1.277 | pmid = 1638986 }}{{cite journal | vauthors = Mao M, Fu G, Wu JS, Zhang QH, Zhou J, Kan LX, Huang QH, He KL, Gu BW, Han ZG, Shen Y, Gu J, Yu YP, Xu SH, Wang YX, Chen SJ, Chen Z | title = Identification of genes expressed in human CD34+ hematopoietic stem/progenitor cells by expressed sequence tags and efficient full-length cDNA cloning | journal = Proc Natl Acad Sci U S A | volume = 95 | issue = 14 | pages = 8175–80 |date=Aug 1998 | pmid = 9653160 | pmc = 20949 | doi =10.1073/pnas.95.14.8175 | doi-access = free | bibcode = 1998PNAS...95.8175M }}{{cite web | title = Entrez Gene: VPS26A vacuolar protein sorting 26 homolog A (S. pombe)| url = https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=9559}}

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. Alternative splicing results in multiple transcript variants encoding different isoforms.

Structure

File:Structural comparison of Vps26 with Arrestins.pngs]]

Vps26 is a 38-kDa subunit that has a two-lobed structure with a polar core that resembles the arrestin family of trafficking adaptor.{{cite journal | vauthors = Collins BM, Norwood SJ, Kerr MC, Mahony D, Seaman MN, Teasdale RD, Owen DJ | title = Structure of Vps26B and mapping of its interaction with the retromer protein complex | journal = Traffic | volume = 9 | issue = 3 | pages = 366–79 |date=March 2008 | pmid = 18088321 | doi = 10.1111/j.1600-0854.2007.00688.x | s2cid = 37113942 | doi-access = }}{{cite journal | vauthors = Shi H, Rojas R, Bonifacino JS, Hurley JH | title = The retromer subunit Vps26 has an arrestin fold and binds Vps35 through its C-terminal domain | journal = Nat. Struct. Mol. Biol. | volume = 13 | issue = 6 | pages = 540–8 |date=June 2006 | pmid = 16732284 | pmc = 1584284 | doi = 10.1038/nsmb1103 }} This fold consist of two related β-sandwich subdomains with a fibronectin type III domain topology. The two domains are joined by a flexible linker and are closely associated by an unusual polar core. Arrestins are regulatory proteins known for connecting G-protein coupled receptors (GPCRs) to clathrin during endocytosis. They play many critical roles in cell signalling and membrane trafficking.{{cite journal | vauthors = Gurevich VV, Gurevich EV | title = The structural basis of arrestin-mediated regulation of G-protein-coupled receptors | journal = Pharmacol. Ther. | volume = 110 | issue = 3 | pages = 465–502 |date=June 2006 | pmid = 16460808 | pmc = 2562282 | doi = 10.1016/j.pharmthera.2005.09.008 }} Both Vps26 and arrestins are composed of two structurally related β-sheet domains forming extensive interfaces with each other, using polar and electrostatic contacts to create interdomain interactions for ligand binding. However, there are significant structural differences between both Vps26 and arrestins. Vps26 protein has extended C-terminal tails that do not contain identifiable clathrin- or AP2-binding sequences, and therefore cannot form stable intramolecular contacts with clathrin and AP2, which has been observed for arrestins. Moreover, Vps26 does not have similar sequences as arrestins for GPCR and phospholipid interactions.{{cite journal | author = Collins BM | title = The structure and function of the retromer protein complex | journal = Traffic | volume = 9 | issue = 11 | pages = 1811–22 |date=November 2008 | pmid = 18541005 | doi = 10.1111/j.1600-0854.2008.00777.x | s2cid = 28028098 | doi-access = }}

Vps26B paralogue

File:Structural differences between Vps26A and Vps26B.png

In yeast, there is only one Vps26 species, whereas there are two Vps26 paralogues (Vps26A and Vps26B) in mammals.{{cite journal | vauthors = Kerr MC, Bennetts JS, Simpson F, Thomas EC, Flegg C, Gleeson PA, Wicking C, Teasdale RD | title = A novel mammalian retromer component, Vps26B | journal = Traffic | volume = 6 | issue = 11 | pages = 991–1001 |date=November 2005 | pmid = 16190980 | doi = 10.1111/j.1600-0854.2005.00328.x | s2cid = 31954489 }}

X-ray crystallography revealed that the structures of both Vps26A and Vps26B share a similar bilobal β-sandwich structure and possess 70% sequence homology. However, these two paralogues distinctly differ on the surface patch within the N-terminal domain, the apex region where the N-terminal and C-terminal domains meet and the disordered C-terminal tail. Vps26B contains several putative serine phosphorylation residues within this disordered tail, which may represent a potential mechanism to modulate the difference between Vps26A and Vps26B. A recent study conducted by Bugarcic et al. pinpointed that this disordered tail on C-terminal region of Vps26B is one of the underlying factors that contributes to the failure for Vps26B-containing Retromer to associate with CI-M6PR, ultimately leading to CI-M6PR degradation, accompanied with increased cathepsin D secretion.{{cite journal | vauthors = Bugarcic A, Zhe Y, Kerr MC, Griffin J, Collins BM, Teasdale RD | title = Vps26A and Vps26B subunits define distinct retromer complexes | journal = Traffic | volume = 12 | issue = 12 | pages = 1759–73 |date=December 2011 | pmid = 21920005 | doi = 10.1111/j.1600-0854.2011.01284.x | s2cid = 24548200 | doi-access = free }}

VPS26A

Structure

Vps26B paralogue

References

Further reading