| Structural highlights
5osi is a 11 chain structure with sequence from Human and Legionella pneumophila subsp. pneumophila 570-co-h. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
| | Ligands: | , |
| Gene: | VPS29, DC15, DC7, MDS007 (HUMAN), VPS35, MEM3, TCCCTA00141 (HUMAN), lp12_2303 (Legionella pneumophila subsp. pneumophila 570-CO-H) |
| 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
[VPS29_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). Has low protein phosphatase activity towards a serine-phosphorylated peptide derived from IGF2R (in vitro).[4] [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).[5]
Publication Abstract from PubMed
Microbial pathogens employ sophisticated virulence strategies to cause infections in humans. The intracellular pathogen Legionella pneumophila encodes RidL to hijack the host scaffold protein VPS29, a component of retromer and retriever complexes critical for endosomal cargo recycling. Here, we determined the crystal structure of L. pneumophila RidL in complex with the human VPS29-VPS35 retromer subcomplex. A hairpin loop protruding from RidL inserts into a conserved pocket on VPS29 that is also used by cellular ligands, such as Tre-2/Bub2/Cdc16 domain family member 5 (TBC1D5) and VPS9-ankyrin repeat protein for VPS29 binding. Consistent with the idea of molecular mimicry in protein interactions, RidL outcompeted TBC1D5 for binding to VPS29. Furthermore, the interaction of RidL with retromer did not interfere with retromer dimerization but was essential for association of RidL with retromer-coated vacuolar and tubular endosomes. Our work thus provides structural and mechanistic evidence into how RidL is targeted to endosomal membranes.
Molecular mechanism for the subversion of the retromer coat by the Legionella effector RidL.,Romano-Moreno M, Rojas AL, Williamson CD, Gershlick DC, Lucas M, Isupov MN, Bonifacino JS, Machner MP, Hierro A Proc Natl Acad Sci U S A. 2017 Dec 11. pii: 1715361115. doi:, 10.1073/pnas.1715361115. PMID:29229824[6]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
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
- ↑ 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
- ↑ Romano-Moreno M, Rojas AL, Williamson CD, Gershlick DC, Lucas M, Isupov MN, Bonifacino JS, Machner MP, Hierro A. Molecular mechanism for the subversion of the retromer coat by the Legionella effector RidL. Proc Natl Acad Sci U S A. 2017 Dec 11. pii: 1715361115. doi:, 10.1073/pnas.1715361115. PMID:29229824 doi:http://dx.doi.org/10.1073/pnas.1715361115
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