5f0p

Structural highlights

Disease

[NRAM2_HUMAN] Microcytic anemia with liver iron overload. The disease is caused by mutations affecting the gene represented in this entry. [VPS35_HUMAN] Defects in VPS35 are the cause of Parkinson disease type 17 (PARK17) [MIM:614203]. PARK17 is an autosomal dominant, adult-onset form of Parkinson disease. Parkinson disease is a complex neurodegenerative disorder characterized by bradykinesia, resting tremor, muscular rigidity and postural instability, as well as by a clinically significant response to treatment with levodopa. The pathology involves the loss of dopaminergic neurons in the substantia nigra and the presence of Lewy bodies (intraneuronal accumulations of aggregated proteins), in surviving neurons in various areas of the brain.^{[1] [2] [3]} [SNX3_HUMAN] MMEP syndrome. The gene represented in this entry may be involved in disease pathogenesis. A chromosomal aberration involving SNX3 has been found in patients with syndromic microphthalmia. Translocation t(6;13)(q21;q12).

Function

[NRAM2_HUMAN] Important in metal transport, in particular iron. Can also transport manganese, cobalt, cadmium, nickel, vanadium and lead. Involved in apical iron uptake into duodenal enterocytes. Involved in iron transport from acidified endosomes into the cytoplasm of erythroid precursor cells. May play an important role in hepatic iron accumulation and tissue iron distribution. May serve to import iron into the mitochondria.^{[4] [5] [6] [7]} [VPS35_HUMAN] Essential component of the retromer complex, a complex required to retrieve lysosomal enzyme receptors (IGF2R and M6PR) from endosomes to the trans-Golgi network. Also required to regulate transcytosis of the polymeric immunoglobulin receptor (pIgR-pIgA).^[8] [SNX3_HUMAN] Phosphoinositide-binding protein required for multivesicular body formation. Specifically binds phosphatidylinositol 3-phosphate (PtdIns(P3)). Plays a role in protein transport between cellular compartments. Promotes stability and cell surface expression of epithelial sodium channel (ENAC) subunits SCNN1A and SCNN1G (By similarity). Not involved in EGFR degradation.^{[9] [10]} [VP26A_HUMAN] Acts as component of the retromer cargo-selective complex (CSC). The CSC is believed to be the core functional component of retromer or respective retromer complex variants acting to prevent missorting of selected transmembrane cargo proteins into the lysosomal degradation pathway. The recruitment of the CSC to the endosomal membrane involves RAB7A and SNX3. The SNX-BAR retromer mediates retrograde transport of cargo proteins from endosomes to the trans-Golgi network (TGN) and is involved in endosome-to-plasma membrane transport for cargo protein recycling. The SNX3-retromer mediates the retrograde endosome-to-TGN transport of WLS distinct from the SNX-BAR retromer pathway. The SNX27-retromer is believed to be involved in endosome-to-plasma membrane trafficking and recycling of a broad spectrum of cargo proteins (Probable). The CSC seems to act as recruitment hub for other proteins, such as the WASH complex and TBC1D5 (Probable). Required for retrograde transport of lysosomal enzyme receptor IGF2R (PubMed:15078902, PubMed:15078903). Required to regulate transcytosis of the polymeric immunoglobulin receptor (pIgR-pIgA) (PubMed:15247922). Required for the endosomal localization of FAM21A (indicative for the WASH complex) (PubMed:22070227). Required for the endosomal localization of TBC1D5 (PubMed:20923837). Mediates retromer cargo reognition of SORL1 and is involved in trafficking of SORL1 implicated in sorting and processing of APP (PubMed:22279231). Involved in retromer-independent lysosomal sorting of F2R (PubMed:16407403). Involved in recycling of ADRB2 (PubMed:21602791). Enhances the affinity of SNX27 for PDZ-binding motifs in cargo proteins (By similarity).[UniProtKB:P40336]^{[11] [12] [13] [14] [15] [16] [17] [18] [19] [20]}

References

1. ↑ Vilarino-Guell C, Wider C, Ross OA, Dachsel JC, Kachergus JM, Lincoln SJ, Soto-Ortolaza AI, Cobb SA, Wilhoite GJ, Bacon JA, Behrouz B, Melrose HL, Hentati E, Puschmann A, Evans DM, Conibear E, Wasserman WW, Aasly JO, Burkhard PR, Djaldetti R, Ghika J, Hentati F, Krygowska-Wajs A, Lynch T, Melamed E, Rajput A, Rajput AH, Solida A, Wu RM, Uitti RJ, Wszolek ZK, Vingerhoets F, Farrer MJ. VPS35 mutations in Parkinson disease. Am J Hum Genet. 2011 Jul 15;89(1):162-7. doi: 10.1016/j.ajhg.2011.06.001. PMID:21763482 doi:10.1016/j.ajhg.2011.06.001
2. ↑ Zimprich A, Benet-Pages A, Struhal W, Graf E, Eck SH, Offman MN, Haubenberger D, Spielberger S, Schulte EC, Lichtner P, Rossle SC, Klopp N, Wolf E, Seppi K, Pirker W, Presslauer S, Mollenhauer B, Katzenschlager R, Foki T, Hotzy C, Reinthaler E, Harutyunyan A, Kralovics R, Peters A, Zimprich F, Brucke T, Poewe W, Auff E, Trenkwalder C, Rost B, Ransmayr G, Winkelmann J, Meitinger T, Strom TM. A mutation in VPS35, encoding a subunit of the retromer complex, causes late-onset Parkinson disease. Am J Hum Genet. 2011 Jul 15;89(1):168-75. doi: 10.1016/j.ajhg.2011.06.008. PMID:21763483 doi:10.1016/j.ajhg.2011.06.008
3. ↑ Lesage S, Condroyer C, Klebe S, Honore A, Tison F, Brefel-Courbon C, Durr A, Brice A. Identification of VPS35 mutations replicated in French families with Parkinson disease. Neurology. 2012 May 1;78(18):1449-50. doi: 10.1212/WNL.0b013e318253d5f2. Epub, 2012 Apr 18. PMID:22517097 doi:10.1212/WNL.0b013e318253d5f2
4. ↑ Mackenzie B, Takanaga H, Hubert N, Rolfs A, Hediger MA. Functional properties of multiple isoforms of human divalent metal-ion transporter 1 (DMT1). Biochem J. 2007 Apr 1;403(1):59-69. PMID:17109629 doi:http://dx.doi.org/10.1042/BJ20061290
5. ↑ Wolff NA, Ghio AJ, Garrick LM, Garrick MD, Zhao L, Fenton RA, Thevenod F. Evidence for mitochondrial localization of divalent metal transporter 1 (DMT1). FASEB J. 2014 May;28(5):2134-45. doi: 10.1096/fj.13-240564. Epub 2014 Jan 21. PMID:24448823 doi:http://dx.doi.org/10.1096/fj.13-240564
6. ↑ Ehrnstorfer IA, Geertsma ER, Pardon E, Steyaert J, Dutzler R. Crystal structure of a SLC11 (NRAMP) transporter reveals the basis for transition-metal ion transport. Nat Struct Mol Biol. 2014 Oct 19. doi: 10.1038/nsmb.2904. PMID:25326704 doi:http://dx.doi.org/10.1038/nsmb.2904
7. ↑ Yanatori I, Yasui Y, Noguchi Y, Kishi F. Inhibition of iron uptake by ferristatin II is exerted through internalization of DMT1 at the plasma membrane. Cell Biol Int. 2015 Apr;39(4):427-34. doi: 10.1002/cbin.10403. Epub 2015 Jan 5. PMID:25491917 doi:http://dx.doi.org/10.1002/cbin.10403
8. ↑ Verges M, Luton F, Gruber C, Tiemann F, Reinders LG, Huang L, Burlingame AL, Haft CR, Mostov KE. The mammalian retromer regulates transcytosis of the polymeric immunoglobulin receptor. Nat Cell Biol. 2004 Aug;6(8):763-9. Epub 2004 Jul 11. PMID:15247922 doi:10.1038/ncb1153
9. ↑ Xu Y, Hortsman H, Seet L, Wong SH, Hong W. SNX3 regulates endosomal function through its PX-domain-mediated interaction with PtdIns(3)P. Nat Cell Biol. 2001 Jul;3(7):658-66. PMID:11433298 doi:http://dx.doi.org/10.1038/35083051
10. ↑ Pons V, Luyet PP, Morel E, Abrami L, van der Goot FG, Parton RG, Gruenberg J. Hrs and SNX3 functions in sorting and membrane invagination within multivesicular bodies. PLoS Biol. 2008 Sep 2;6(9):e214. doi: 10.1371/journal.pbio.0060214. PMID:18767904 doi:http://dx.doi.org/10.1371/journal.pbio.0060214
11. ↑ Seaman MN. Cargo-selective endosomal sorting for retrieval to the Golgi requires retromer. J Cell Biol. 2004 Apr;165(1):111-22. PMID:15078902 doi:http://dx.doi.org/10.1083/jcb.200312034
12. ↑ Arighi CN, Hartnell LM, Aguilar RC, Haft CR, Bonifacino JS. Role of the mammalian retromer in sorting of the cation-independent mannose 6-phosphate receptor. J Cell Biol. 2004 Apr;165(1):123-33. PMID:15078903 doi:http://dx.doi.org/10.1083/jcb.200312055
13. ↑ Verges M, Luton F, Gruber C, Tiemann F, Reinders LG, Huang L, Burlingame AL, Haft CR, Mostov KE. The mammalian retromer regulates transcytosis of the polymeric immunoglobulin receptor. Nat Cell Biol. 2004 Aug;6(8):763-9. Epub 2004 Jul 11. PMID:15247922 doi:10.1038/ncb1153
14. ↑ Gullapalli A, Wolfe BL, Griffin CT, Magnuson T, Trejo J. An essential role for SNX1 in lysosomal sorting of protease-activated receptor-1: evidence for retromer-, Hrs-, and Tsg101-independent functions of sorting nexins. Mol Biol Cell. 2006 Mar;17(3):1228-38. Epub 2006 Jan 11. PMID:16407403 doi:http://dx.doi.org/10.1091/mbc.E05-09-0899
15. ↑ Harbour ME, Breusegem SY, Seaman MN. Recruitment of the endosomal WASH complex is mediated by the extended 'tail' of Fam21 binding to the retromer protein Vps35. Biochem J. 2012 Feb 15;442(1):209-20. doi: 10.1042/BJ20111761. PMID:22070227 doi:http://dx.doi.org/10.1042/BJ20111761
16. ↑ Fjorback AW, Seaman M, Gustafsen C, Mehmedbasic A, Gokool S, Wu C, Militz D, Schmidt V, Madsen P, Nyengaard JR, Willnow TE, Christensen EI, Mobley WB, Nykjaer A, Andersen OM. Retromer binds the FANSHY sorting motif in SorLA to regulate amyloid precursor protein sorting and processing. J Neurosci. 2012 Jan 25;32(4):1467-80. doi: 10.1523/JNEUROSCI.2272-11.2012. PMID:22279231 doi:http://dx.doi.org/10.1523/JNEUROSCI.2272-11.2012
17. ↑ Harbour ME, Breusegem SY, Antrobus R, Freeman C, Reid E, Seaman MN. The cargo-selective retromer complex is a recruiting hub for protein complexes that regulate endosomal tubule dynamics. J Cell Sci. 2010 Nov 1;123(Pt 21):3703-17. doi: 10.1242/jcs.071472. Epub 2010 Oct, 5. PMID:20923837 doi:http://dx.doi.org/10.1242/jcs.071472
18. ↑ Temkin P, Lauffer B, Jager S, Cimermancic P, Krogan NJ, von Zastrow M. SNX27 mediates retromer tubule entry and endosome-to-plasma membrane trafficking of signalling receptors. Nat Cell Biol. 2011 Jun;13(6):715-21. doi: 10.1038/ncb2252. Epub 2011 May 22. PMID:21602791 doi:http://dx.doi.org/10.1038/ncb2252
19. ↑ Harterink M, Port F, Lorenowicz MJ, McGough IJ, Silhankova M, Betist MC, van Weering JR, van Heesbeen RG, Middelkoop TC, Basler K, Cullen PJ, Korswagen HC. A SNX3-dependent retromer pathway mediates retrograde transport of the Wnt sorting receptor Wntless and is required for Wnt secretion. Nat Cell Biol. 2011 Jul 3;13(8):914-23. doi: 10.1038/ncb2281. PMID:21725319 doi:http://dx.doi.org/10.1038/ncb2281
20. ↑ Steinberg F, Gallon M, Winfield M, Thomas EC, Bell AJ, Heesom KJ, Tavare JM, Cullen PJ. A global analysis of SNX27-retromer assembly and cargo specificity reveals a function in glucose and metal ion transport. Nat Cell Biol. 2013 May;15(5):461-71. doi: 10.1038/ncb2721. Epub 2013 Apr 7. PMID:23563491 doi:http://dx.doi.org/10.1038/ncb2721
21. ↑ Lucas M, Gershlick DC, Vidaurrazaga A, Rojas AL, Bonifacino JS, Hierro A. Structural Mechanism for Cargo Recognition by the Retromer Complex. Cell. 2016 Dec 1;167(6):1623-1635.e14. doi: 10.1016/j.cell.2016.10.056. Epub 2016, Nov 23. PMID:27889239 doi:http://dx.doi.org/10.1016/j.cell.2016.10.056