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| | <StructureSection load='6stf' size='340' side='right'caption='[[6stf]], [[Resolution|resolution]] 2.40Å' scene=''> | | <StructureSection load='6stf' size='340' side='right'caption='[[6stf]], [[Resolution|resolution]] 2.40Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[6stf]] is a 5 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=6STF OCA]. For a <b>guided tour on the structure components</b> use [http://proteopedia.org/fgij/fg.htm?mol=6STF FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[6stf]] is a 5 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=6STF OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6STF FirstGlance]. <br> |
| - | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=GDP:GUANOSINE-5-DIPHOSPHATE'>GDP</scene>, <scene name='pdbligand=MG:MAGNESIUM+ION'>MG</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]] 2.4Å</td></tr> |
| - | <tr id='NonStdRes'><td class="sblockLbl"><b>[[Non-Standard_Residue|NonStd Res:]]</b></td><td class="sblockDat"><scene name='pdbligand=SEP:PHOSPHOSERINE'>SEP</scene></td></tr> | + | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=GDP:GUANOSINE-5-DIPHOSPHATE'>GDP</scene>, <scene name='pdbligand=MG:MAGNESIUM+ION'>MG</scene>, <scene name='pdbligand=SEP:PHOSPHOSERINE'>SEP</scene></td></tr> |
| - | <tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[4lhv|4lhv]]</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=6stf FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6stf OCA], [https://pdbe.org/6stf PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6stf RCSB], [https://www.ebi.ac.uk/pdbsum/6stf PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6stf ProSAT]</span></td></tr> |
| - | <tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">RAB8A, MEL, RAB8 ([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://proteopedia.org/fgij/fg.htm?mol=6stf FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6stf OCA], [http://pdbe.org/6stf PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6stf RCSB], [http://www.ebi.ac.uk/pdbsum/6stf PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6stf ProSAT]</span></td></tr> | + | |
| | </table> | | </table> |
| | == Function == | | == Function == |
| - | [[http://www.uniprot.org/uniprot/RAB8A_HUMAN RAB8A_HUMAN]] May be involved in vesicular trafficking and neurotransmitter release. Together with RAB11A, RAB3IP, the exocyst complex, PARD3, PRKCI, ANXA2, CDC42 and DNMBP promotes transcytosis of PODXL to the apical membrane initiation sites (AMIS), apical surface formation and lumenogenesis. Together with MYO5B and RAB11A participates in epithelial cell polarization.<ref>PMID:20890297</ref> <ref>PMID:21282656</ref> | + | [https://www.uniprot.org/uniprot/RAB8A_HUMAN RAB8A_HUMAN] May be involved in vesicular trafficking and neurotransmitter release. Together with RAB11A, RAB3IP, the exocyst complex, PARD3, PRKCI, ANXA2, CDC42 and DNMBP promotes transcytosis of PODXL to the apical membrane initiation sites (AMIS), apical surface formation and lumenogenesis. Together with MYO5B and RAB11A participates in epithelial cell polarization.<ref>PMID:20890297</ref> <ref>PMID:21282656</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 6stf" style="background-color:#fffaf0;"></div> | | <div class="pdbe-citations 6stf" style="background-color:#fffaf0;"></div> |
| | + | |
| | + | ==See Also== |
| | + | *[[Ras-related protein Rab 3D structures|Ras-related protein Rab 3D structures]] |
| | == References == | | == References == |
| | <references/> | | <references/> |
| | __TOC__ | | __TOC__ |
| | </StructureSection> | | </StructureSection> |
| - | [[Category: Human]] | + | [[Category: Homo sapiens]] |
| | [[Category: Large Structures]] | | [[Category: Large Structures]] |
| - | [[Category: Braeuning, B]] | + | [[Category: Braeuning B]] |
| - | [[Category: Groll, M]] | + | [[Category: Groll M]] |
| - | [[Category: Itzen, A]] | + | [[Category: Itzen A]] |
| - | [[Category: Kachariya, N]] | + | [[Category: Kachariya N]] |
| - | [[Category: Lai, Y]] | + | [[Category: Lai Y]] |
| - | [[Category: Mulholland, K]] | + | [[Category: Mulholland K]] |
| - | [[Category: Muqit, M M.K]] | + | [[Category: Muqit MMK]] |
| - | [[Category: Sattler, M]] | + | [[Category: Sattler M]] |
| - | [[Category: Toth, R]] | + | [[Category: Toth R]] |
| - | [[Category: Vieweg, S]] | + | [[Category: Vieweg S]] |
| - | [[Category: Parkinson disease]]
| + | |
| - | [[Category: Phosphorylation]]
| + | |
| - | [[Category: Sf3 motif]]
| + | |
| - | [[Category: Signaling protein]]
| + | |
| - | [[Category: Small g-protein]]
| + | |
| Structural highlights
Function
RAB8A_HUMAN May be involved in vesicular trafficking and neurotransmitter release. Together with RAB11A, RAB3IP, the exocyst complex, PARD3, PRKCI, ANXA2, CDC42 and DNMBP promotes transcytosis of PODXL to the apical membrane initiation sites (AMIS), apical surface formation and lumenogenesis. Together with MYO5B and RAB11A participates in epithelial cell polarization.[1] [2]
Publication Abstract from PubMed
Loss of function mutations in the PINK1 kinase are causal for autosomal recessive Parkinson's disease (PD) whilst gain of function mutations in the LRRK2 kinase cause autosomal dominant PD. PINK1 indirectly regulates the phosphorylation of a subset of Rab GTPases at a conserved Serine111 (Ser111) residue within the SF3 motif. Using genetic code expansion technologies we have produced stoichiometric Ser111-phosphorylated Rab8A revealing impaired interactions with its cognate guanine nucleotide exchange factor (GEF) and GTPase activating protein (GAP). In a screen for Rab8A kinases we identify TAK1 and MST3 kinases that can efficiently phosphorylate the Switch II residue Threonine72 (Thr72) in a similar manner as LRRK2 in vitro. Strikingly we demonstrate that Ser111 phosphorylation negatively regulates the ability of LRRK2 but not MST3 or TAK1 to phosphorylate Thr72 of recombinant nucleotide-bound Rab8A in vitro and demonstrate an interplay of PINK1- and LRRK2-mediated phosphorylation of Rab8A in transfected HEK293 cells. Finally, we present the crystal structure of Ser111-phosphorylated Rab8A and NMR structure of Ser111-phosphorylated Rab1B. The structures reveal that the phosphorylated SF3 motif does not induce any major changes, but may interfere with effector-Switch II interactions through intramolecular H-bond formation and/or charge effects with Arg79. Overall, we demonstrate antagonistic regulation between PINK1-dependent Ser111 phosphorylation and LRRK2-mediated Thr72 phosphorylation of Rab8A indicating a potential crosstalk between PINK1-regulated mitochondrial homeostasis and LRRK2 signalling that requires further investigation in vivo.
PINK1-dependent phosphorylation of Serine111 within the SF3 motif of Rab GTPases impairs effector interactions and LRRK2 mediated phosphorylation at Threonine72.,Vieweg S, Mulholland K, Brauning B, Kacharia N, Lai YC, Toth R, Singh PK, Volpi I, Sattler M, Groll M, Itzen A, Muqit MMK Biochem J. 2020 Mar 30. pii: 222508. doi: 10.1042/BCJ20190664. PMID:32227113[3]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ Bryant DM, Datta A, Rodriguez-Fraticelli AE, Peranen J, Martin-Belmonte F, Mostov KE. A molecular network for de novo generation of the apical surface and lumen. Nat Cell Biol. 2010 Nov;12(11):1035-45. doi: 10.1038/ncb2106. Epub 2010 Oct 3. PMID:20890297 doi:10.1038/ncb2106
- ↑ Roland JT, Bryant DM, Datta A, Itzen A, Mostov KE, Goldenring JR. Rab GTPase-Myo5B complexes control membrane recycling and epithelial polarization. Proc Natl Acad Sci U S A. 2011 Feb 15;108(7):2789-94. doi:, 10.1073/pnas.1010754108. Epub 2011 Jan 31. PMID:21282656 doi:10.1073/pnas.1010754108
- ↑ Vieweg S, Mulholland K, Brauning B, Kacharia N, Lai YC, Toth R, Singh PK, Volpi I, Sattler M, Groll M, Itzen A, Muqit MMK. PINK1-dependent phosphorylation of Serine111 within the SF3 motif of Rab GTPases impairs effector interactions and LRRK2 mediated phosphorylation at Threonine72. Biochem J. 2020 Mar 30. pii: 222508. doi: 10.1042/BCJ20190664. PMID:32227113 doi:http://dx.doi.org/10.1042/BCJ20190664
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