5f0l

Structure of retromer VPS26-VPS35 subunits bound to SNX3 and DMT1

Structural highlights

5f0l is a 4 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:	X-ray diffraction, Resolution 3.2Å
Ligands:	EDO, GOL, SO4
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Disease

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]

Function

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).^[4]

Publication Abstract from PubMed

Retromer is a multi-protein complex that recycles transmembrane cargo from endosomes to the trans-Golgi network and the plasma membrane. Defects in retromer impair various cellular processes and underlie some forms of Alzheimer's disease and Parkinson's disease. Although retromer was discovered over 15 years ago, the mechanisms for cargo recognition and recruitment to endosomes have remained elusive. Here, we present an X-ray crystallographic analysis of a four-component complex comprising the VPS26 and VPS35 subunits of retromer, the sorting nexin SNX3, and a recycling signal from the divalent cation transporter DMT1-II. This analysis identifies a binding site for canonical recycling signals at the interface between VPS26 and SNX3. In addition, the structure highlights a network of cooperative interactions among the VPS subunits, SNX3, and cargo that couple signal-recognition to membrane recruitment.

Structural Mechanism for Cargo Recognition by the Retromer Complex.,Lucas M, Gershlick DC, Vidaurrazaga A, Rojas AL, Bonifacino JS, Hierro A Cell. 2016 Dec 1;167(6):1623-1635.e14. doi: 10.1016/j.cell.2016.10.056. Epub 2016, Nov 23. PMID:27889239^[5]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

References

↑ 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
↑ 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
↑ 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
↑ 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
↑ 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:https://dx.doi.org/10.1016/j.cell.2016.10.056

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OCA

[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] 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

[5] 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:https://dx.doi.org/10.1016/j.cell.2016.10.056

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5f0l

Structure of retromer VPS26-VPS35 subunits bound to SNX3 and DMT1

Structural highlights

Disease

Function

Publication Abstract from PubMed

See Also

References

Contents

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