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| | ==Structure of retromer VPS26-VPS35 subunits bound to SNX3 and DMT1(L557M) (SeMet labeled)== | | ==Structure of retromer VPS26-VPS35 subunits bound to SNX3 and DMT1(L557M) (SeMet labeled)== |
| - | <StructureSection load='5f0p' size='340' side='right' caption='[[5f0p]], [[Resolution|resolution]] 2.78Å' scene=''> | + | <StructureSection load='5f0p' size='340' side='right'caption='[[5f0p]], [[Resolution|resolution]] 2.78Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[5f0p]] is a 4 chain structure with sequence from [http://en.wikipedia.org/wiki/Human Human]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5F0P OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5F0P FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[5f0p]] is a 4 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5F0P OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=5F0P FirstGlance]. <br> |
| - | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=EDO:1,2-ETHANEDIOL'>EDO</scene>, <scene name='pdbligand=GOL:GLYCEROL'>GOL</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene>, <scene name='pdbligand=ZN:ZINC+ION'>ZN</scene></td></tr> | + | </td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2.78Å</td></tr> |
| - | <tr id='NonStdRes'><td class="sblockLbl"><b>[[Non-Standard_Residue|NonStd Res:]]</b></td><td class="sblockDat"><scene name='pdbligand=MSE:SELENOMETHIONINE'>MSE</scene></td></tr> | + | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=EDO:1,2-ETHANEDIOL'>EDO</scene>, <scene name='pdbligand=GOL:GLYCEROL'>GOL</scene>, <scene name='pdbligand=MSE:SELENOMETHIONINE'>MSE</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene>, <scene name='pdbligand=ZN:ZINC+ION'>ZN</scene></td></tr> |
| - | <tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[2r17|2r17]], [[2fau|2fau]], [[5f0j|5f0j]], [[5f0k|5f0k]], [[5f0l|5f0l]], [[5f0m|5f0m]]</td></tr> | + | <tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=5f0p FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5f0p OCA], [https://pdbe.org/5f0p PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=5f0p RCSB], [https://www.ebi.ac.uk/pdbsum/5f0p PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=5f0p ProSAT]</span></td></tr> |
| - | <tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">VPS35, MEM3, TCCCTA00141 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN]), VPS26A, VPS26 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN]), SNX3 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN]), SLC11A2, DCT1, DMT1, NRAMP2, OK/SW-cl.20 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</td></tr>
| + | |
| - | <tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5f0p FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5f0p OCA], [http://pdbe.org/5f0p PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5f0p RCSB], [http://www.ebi.ac.uk/pdbsum/5f0p PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5f0p ProSAT]</span></td></tr> | + | |
| | </table> | | </table> |
| | == Disease == | | == Disease == |
| - | [[http://www.uniprot.org/uniprot/NRAM2_HUMAN NRAM2_HUMAN]] Microcytic anemia with liver iron overload. The disease is caused by mutations affecting the gene represented in this entry. [[http://www.uniprot.org/uniprot/VPS35_HUMAN VPS35_HUMAN]] Defects in VPS35 are the cause of Parkinson disease type 17 (PARK17) [MIM:[http://omim.org/entry/614203 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.<ref>PMID:21763482</ref> <ref>PMID:21763483</ref> <ref>PMID:22517097</ref> [[http://www.uniprot.org/uniprot/SNX3_HUMAN 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). | + | [https://www.uniprot.org/uniprot/NRAM2_HUMAN NRAM2_HUMAN] Microcytic anemia with liver iron overload. The disease is caused by mutations affecting the gene represented in this entry. |
| | == Function == | | == Function == |
| - | [[http://www.uniprot.org/uniprot/NRAM2_HUMAN 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.<ref>PMID:17109629</ref> <ref>PMID:24448823</ref> <ref>PMID:25326704</ref> <ref>PMID:25491917</ref> [[http://www.uniprot.org/uniprot/VPS35_HUMAN 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).<ref>PMID:15247922</ref> [[http://www.uniprot.org/uniprot/SNX3_HUMAN 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.<ref>PMID:11433298</ref> <ref>PMID:18767904</ref> [[http://www.uniprot.org/uniprot/VP26A_HUMAN 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]<ref>PMID:15078902</ref> <ref>PMID:15078903</ref> <ref>PMID:15247922</ref> <ref>PMID:16407403</ref> <ref>PMID:22070227</ref> <ref>PMID:22279231</ref> <ref>PMID:20923837</ref> <ref>PMID:21602791</ref> <ref>PMID:21725319</ref> <ref>PMID:23563491</ref> | + | [https://www.uniprot.org/uniprot/NRAM2_HUMAN 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.<ref>PMID:17109629</ref> <ref>PMID:24448823</ref> <ref>PMID:25326704</ref> <ref>PMID:25491917</ref> |
| | <div style="background-color:#fffaf0;"> | | <div style="background-color:#fffaf0;"> |
| | == Publication Abstract from PubMed == | | == Publication Abstract from PubMed == |
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| | </div> | | </div> |
| | <div class="pdbe-citations 5f0p" style="background-color:#fffaf0;"></div> | | <div class="pdbe-citations 5f0p" style="background-color:#fffaf0;"></div> |
| | + | |
| | + | ==See Also== |
| | + | *[[Sorting nexin 3D structures|Sorting nexin 3D structures]] |
| | + | *[[Vacuolar protein sorting-associated protein 3D structures|Vacuolar protein sorting-associated protein 3D structures]] |
| | == References == | | == References == |
| | <references/> | | <references/> |
| | __TOC__ | | __TOC__ |
| | </StructureSection> | | </StructureSection> |
| - | [[Category: Human]] | + | [[Category: Homo sapiens]] |
| - | [[Category: Bonifacino, J S]] | + | [[Category: Large Structures]] |
| - | [[Category: Gershlick, D]] | + | [[Category: Bonifacino JS]] |
| - | [[Category: Hierro, A]] | + | [[Category: Gershlick D]] |
| - | [[Category: Lucas, M]] | + | [[Category: Hierro A]] |
| - | [[Category: Rojas, A L]] | + | [[Category: Lucas M]] |
| - | [[Category: Vidaurrazaga, A]] | + | [[Category: Rojas AL]] |
| - | [[Category: Protein transport]]
| + | [[Category: Vidaurrazaga A]] |
| - | [[Category: Retromer]]
| + | |
| - | [[Category: Sorting nexin]]
| + | |
| Structural highlights
5f0p 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 2.78Å |
| Ligands: | , , , , |
| Resources: | FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT |
Disease
NRAM2_HUMAN Microcytic anemia with liver iron overload. The disease is caused by mutations affecting the gene represented in this entry.
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.[1] [2] [3] [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.
See Also
References
- ↑ 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
- ↑ 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
- ↑ 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
- ↑ 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
- ↑ 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
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