View source for 6stg


==Human Rab8a phosphorylated at Ser111 in complex with GPPNP==
<StructureSection load='6stg' size='340' side='right'caption='[[6stg]], [[Resolution|resolution]] 2.50&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6STG OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6STG FirstGlance]. <br>
</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2.5&#8491;</td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=GNP:PHOSPHOAMINOPHOSPHONIC+ACID-GUANYLATE+ESTER'>GNP</scene>, <scene name='pdbligand=MG:MAGNESIUM+ION'>MG</scene>, <scene name='pdbligand=SEP:PHOSPHOSERINE'>SEP</scene>, <scene name='pdbligand=TRS:2-AMINO-2-HYDROXYMETHYL-PROPANE-1,3-DIOL'>TRS</scene></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=6stg FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6stg OCA], [https://pdbe.org/6stg PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6stg RCSB], [https://www.ebi.ac.uk/pdbsum/6stg PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6stg ProSAT]</span></td></tr>
</table>
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== 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<ref>PMID:32227113</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 6stg" style="background-color:#fffaf0;"></div>

==See Also==
*[[Ras-related protein Rab 3D structures|Ras-related protein Rab 3D structures]]
== References ==
<references/>
__TOC__
</StructureSection>
[[Category: Large Structures]]
[[Category: Braeuning B]]
[[Category: Groll M]]
[[Category: Itzen A]]
[[Category: Kachariya N]]
[[Category: Lai Y]]
[[Category: Mulholland K]]
[[Category: Muqit MMK]]
[[Category: Sattler M]]
[[Category: Toth R]]
[[Category: Vieweg S]]