6ff8: Difference between revisions
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==Crystal structure of uncomplexed Rab32 in the active GTP-bound state at 2.13 Angstrom resolution== | ==Crystal structure of uncomplexed Rab32 in the active GTP-bound state at 2.13 Angstrom resolution== | ||
<StructureSection load='6ff8' size='340' side='right' caption='[[6ff8]], [[Resolution|resolution]] 2.13Å' scene=''> | <StructureSection load='6ff8' size='340' side='right'caption='[[6ff8]], [[Resolution|resolution]] 2.13Å' scene=''> | ||
== Structural highlights == | == Structural highlights == | ||
<table><tr><td colspan='2'>[[6ff8]] is a 2 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6FF8 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6FF8 FirstGlance]. <br> | <table><tr><td colspan='2'>[[6ff8]] is a 2 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=6FF8 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6FF8 FirstGlance]. <br> | ||
</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=GTP:GUANOSINE-5-TRIPHOSPHATE'>GTP</scene>, <scene name='pdbligand=MG:MAGNESIUM+ION'>MG</scene></td></tr> | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=GTP:GUANOSINE-5-TRIPHOSPHATE'>GTP</scene>, <scene name='pdbligand=MG:MAGNESIUM+ION'>MG</scene></td></tr> | ||
<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">RAB32 ([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=6ff8 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6ff8 OCA], [http://pdbe.org/6ff8 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6ff8 RCSB], [http://www.ebi.ac.uk/pdbsum/6ff8 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6ff8 ProSAT]</span></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=6ff8 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6ff8 OCA], [http://pdbe.org/6ff8 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6ff8 RCSB], [http://www.ebi.ac.uk/pdbsum/6ff8 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6ff8 ProSAT]</span></td></tr> | ||
</table> | </table> | ||
== Function == | == Function == | ||
[[http://www.uniprot.org/uniprot/RAB32_HUMAN RAB32_HUMAN]] Acts as an A-kinase anchoring protein by binding to the type II regulatory subunit of protein kinase A and anchoring it to the mitochondrion. Also involved in synchronization of mitochondrial fission. Plays a role in the maturation of phagosomes that engulf pathogens, such as S.aureus and M.tuberculosis.<ref>PMID:12186851</ref> <ref>PMID:21255211</ref> | [[http://www.uniprot.org/uniprot/RAB32_HUMAN RAB32_HUMAN]] Acts as an A-kinase anchoring protein by binding to the type II regulatory subunit of protein kinase A and anchoring it to the mitochondrion. Also involved in synchronization of mitochondrial fission. Plays a role in the maturation of phagosomes that engulf pathogens, such as S.aureus and M.tuberculosis.<ref>PMID:12186851</ref> <ref>PMID:21255211</ref> | ||
<div style="background-color:#fffaf0;"> | |||
== Publication Abstract from PubMed == | |||
LRRK2 is a multi-domain Ser/Thr kinase that is associated with inherited and sporadic cases of Parkinson's disease. Many mutations linked to disease are associated within a central ROC-COR regulatory region and the subsequent kinase domain, leading to enhanced catalytic activity. The N-terminus of human LRRK2 consists of armadillo repeat motifs (ARMs) followed by ankyrin repeats (ANKs). Recently, Rab GTPases have emerged as key players in LRRK2 function, both as substrates of the kinase, and as regulators of the catalytic activity. Rabs recruit effector proteins via their GTP-dependent switch 1 and 2 regions to distinct sub-cellular compartments to regulate membrane trafficking. LRRK2 phosphorylates Rab8, Rab10 and Rab12 in switch 2, and this activity is regulated via interactions with Rab29. Furthermore, the related Rab32-subfamily GTPases, Rab32 and Rab38, have also been shown to interact with LRRK2. Here, we have mapped the interactions of the Rab32-subfamily to the ARM domain of LRRK2. The complexes are dependent on the GTP state of the Rabs in vitro, implying that LRRK2 may be an effector of the Rab32-subfamily of small GTPases. X-ray crystal structures of the Rab32-family GTPases and subsequent mutational studies reveal that a positively charged residue in switch 1 is critical for binding of Rab32/38 to LRRK2. Homology modelling and mutational analyses of the ARM domain point to a patch of negatively charged residues that contribute to complex formation. These structural and biochemical studies provide a framework for understanding the molecular basis for Rab regulation of LRRK2 and its role in Parkinson's disease. | |||
LRRK2 binds to the Rab32 subfamily in a GTP-dependent manner via its armadillo domain.,McGrath E, Waschbusch D, Baker BM, Khan AR Small GTPases. 2019 Sep 25:1-14. doi: 10.1080/21541248.2019.1666623. PMID:31552791<ref>PMID:31552791</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
</div> | |||
<div class="pdbe-citations 6ff8" style="background-color:#fffaf0;"></div> | |||
== References == | == References == | ||
<references/> | <references/> | ||
__TOC__ | __TOC__ | ||
</StructureSection> | </StructureSection> | ||
[[Category: Human]] | |||
[[Category: Large Structures]] | |||
[[Category: Kecman, T]] | [[Category: Kecman, T]] | ||
[[Category: Khan, A R]] | [[Category: Khan, A R]] | ||
Latest revision as of 11:40, 27 November 2019
Crystal structure of uncomplexed Rab32 in the active GTP-bound state at 2.13 Angstrom resolutionCrystal structure of uncomplexed Rab32 in the active GTP-bound state at 2.13 Angstrom resolution
Structural highlights
Function[RAB32_HUMAN] Acts as an A-kinase anchoring protein by binding to the type II regulatory subunit of protein kinase A and anchoring it to the mitochondrion. Also involved in synchronization of mitochondrial fission. Plays a role in the maturation of phagosomes that engulf pathogens, such as S.aureus and M.tuberculosis.[1] [2] Publication Abstract from PubMedLRRK2 is a multi-domain Ser/Thr kinase that is associated with inherited and sporadic cases of Parkinson's disease. Many mutations linked to disease are associated within a central ROC-COR regulatory region and the subsequent kinase domain, leading to enhanced catalytic activity. The N-terminus of human LRRK2 consists of armadillo repeat motifs (ARMs) followed by ankyrin repeats (ANKs). Recently, Rab GTPases have emerged as key players in LRRK2 function, both as substrates of the kinase, and as regulators of the catalytic activity. Rabs recruit effector proteins via their GTP-dependent switch 1 and 2 regions to distinct sub-cellular compartments to regulate membrane trafficking. LRRK2 phosphorylates Rab8, Rab10 and Rab12 in switch 2, and this activity is regulated via interactions with Rab29. Furthermore, the related Rab32-subfamily GTPases, Rab32 and Rab38, have also been shown to interact with LRRK2. Here, we have mapped the interactions of the Rab32-subfamily to the ARM domain of LRRK2. The complexes are dependent on the GTP state of the Rabs in vitro, implying that LRRK2 may be an effector of the Rab32-subfamily of small GTPases. X-ray crystal structures of the Rab32-family GTPases and subsequent mutational studies reveal that a positively charged residue in switch 1 is critical for binding of Rab32/38 to LRRK2. Homology modelling and mutational analyses of the ARM domain point to a patch of negatively charged residues that contribute to complex formation. These structural and biochemical studies provide a framework for understanding the molecular basis for Rab regulation of LRRK2 and its role in Parkinson's disease. LRRK2 binds to the Rab32 subfamily in a GTP-dependent manner via its armadillo domain.,McGrath E, Waschbusch D, Baker BM, Khan AR Small GTPases. 2019 Sep 25:1-14. doi: 10.1080/21541248.2019.1666623. PMID:31552791[3] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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