6xr4

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==Integrative in situ structure of Parkinsons disease-linked human LRRK2==
==Integrative in situ structure of Parkinsons disease-linked human LRRK2==
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<StructureSection load='6xr4' size='340' side='right'caption='[[6xr4]]' scene=''>
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<StructureSection load='6xr4' size='340' side='right'caption='[[6xr4]], [[Resolution|resolution]] 14.00&Aring;' scene=''>
== Structural highlights ==
== Structural highlights ==
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<table><tr><td colspan='2'>Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6XR4 OCA]. For a <b>guided tour on the structure components</b> use [http://proteopedia.org/fgij/fg.htm?mol=6XR4 FirstGlance]. <br>
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<table><tr><td colspan='2'>[[6xr4]] is a 2 chain structure with sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6XR4 OCA]. For a <b>guided tour on the structure components</b> use [http://proteopedia.org/fgij/fg.htm?mol=6XR4 FirstGlance]. <br>
</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=6xr4 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6xr4 OCA], [http://pdbe.org/6xr4 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6xr4 RCSB], [http://www.ebi.ac.uk/pdbsum/6xr4 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6xr4 ProSAT]</span></td></tr>
</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=6xr4 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6xr4 OCA], [http://pdbe.org/6xr4 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6xr4 RCSB], [http://www.ebi.ac.uk/pdbsum/6xr4 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6xr4 ProSAT]</span></td></tr>
</table>
</table>
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== Disease ==
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[[http://www.uniprot.org/uniprot/LRRK2_HUMAN LRRK2_HUMAN]] Defects in LRRK2 are the cause of Parkinson disease type 8 (PARK8) [MIM:[http://omim.org/entry/607060 607060]]. A slowly progressive neurodegenerative disorder characterized by bradykinesia, rigidity, resting tremor, postural instability, neuronal loss in the substantia nigra, and the presence of neurofibrillary MAPT (tau)-positive and Lewy bodies in some patients.<ref>PMID:21850687</ref> <ref>PMID:16321986</ref> <ref>PMID:16269541</ref> <ref>PMID:15541309</ref> <ref>PMID:15541308</ref> <ref>PMID:16081470</ref> <ref>PMID:16087219</ref> <ref>PMID:15726496</ref> <ref>PMID:15732108</ref> <ref>PMID:15852371</ref> <ref>PMID:16240353</ref> <ref>PMID:15880653</ref> <ref>PMID:15929036</ref> <ref>PMID:16251215</ref> <ref>PMID:16272164</ref> <ref>PMID:16333314</ref> <ref>PMID:16272257</ref> <ref>PMID:15680455</ref> <ref>PMID:15680456</ref> <ref>PMID:15680457</ref> <ref>PMID:15811454</ref> <ref>PMID:16250030</ref> <ref>PMID:16172858</ref> <ref>PMID:16157901</ref> <ref>PMID:16247070</ref> <ref>PMID:16157908</ref> <ref>PMID:16157909</ref> <ref>PMID:15925109</ref> <ref>PMID:16298482</ref> <ref>PMID:16102999</ref> <ref>PMID:16533964</ref> <ref>PMID:17019612</ref> <ref>PMID:18213618</ref> <ref>PMID:21641266</ref>
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== Function ==
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[[http://www.uniprot.org/uniprot/LRRK2_HUMAN LRRK2_HUMAN]] May play a role in the phosphorylation of proteins central to Parkinson disease. Phosphorylates PRDX3. May also have GTPase activity. Positively regulates autophagy through a calcium-dependent activation of the CaMKK/AMPK signaling pathway. The process involves activation of nicotinic acid adenine dinucleotide phosphate (NAADP) receptors, increase in lysosomal pH, and calcium release from lysosomes.<ref>PMID:16352719</ref> <ref>PMID:20949042</ref> <ref>PMID:21850687</ref> <ref>PMID:22012985</ref>
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<div style="background-color:#fffaf0;">
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== Publication Abstract from PubMed ==
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Mutations in leucine-rich repeat kinase 2 (LRRK2) are the most frequent cause of familial Parkinson's disease. LRRK2 is a multi-domain protein containing a kinase and GTPase. Using correlative light and electron microscopy, in situ cryo-electron tomography, and subtomogram analysis, we reveal a 14-A structure of LRRK2 bearing a pathogenic mutation that oligomerizes as a right-handed double helix around microtubules, which are left-handed. Using integrative modeling, we determine the architecture of LRRK2, showing that the GTPase and kinase are in close proximity, with the GTPase closer to the microtubule surface, whereas the kinase is exposed to the cytoplasm. We identify two oligomerization interfaces mediated by non-catalytic domains. Mutation of one of these abolishes LRRK2 microtubule-association. Our work demonstrates the power of cryo-electron tomography to generate models of previously unsolved structures in their cellular environment.
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The In Situ Structure of Parkinson's Disease-Linked LRRK2.,Watanabe R, Buschauer R, Bohning J, Audagnotto M, Lasker K, Lu TW, Boassa D, Taylor S, Villa E Cell. 2020 Aug 7. pii: S0092-8674(20)30995-8. doi: 10.1016/j.cell.2020.08.004. PMID:32783917<ref>PMID:32783917</ref>
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From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
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</div>
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<div class="pdbe-citations 6xr4" style="background-color:#fffaf0;"></div>
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== References ==
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<references/>
__TOC__
__TOC__
</StructureSection>
</StructureSection>
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[[Category: Homo sapiens]]
[[Category: Large Structures]]
[[Category: Large Structures]]
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[[Category: Audagnotto M]]
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[[Category: Audagnotto, M]]
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[[Category: Lasker K]]
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[[Category: Lasker, K]]
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[[Category: Villa E]]
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[[Category: Villa, E]]
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[[Category: Gtpase]]
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[[Category: Kinase]]
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[[Category: Parkinson's disease]]
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[[Category: Pseudo-kinase]]
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[[Category: Signaling protein]]
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[[Category: Transferase]]

Revision as of 11:37, 26 August 2020

Integrative in situ structure of Parkinsons disease-linked human LRRK2

PDB ID 6xr4

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