View source for 8vh4


==Cryo-EM structure of Rab12-LRRK2 complex in the LRRK2 monomer state==
<StructureSection load='8vh4' size='340' side='right'caption='[[8vh4]], [[Resolution|resolution]] 4.10&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[8vh4]] is a 2 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=8VH4 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=8VH4 FirstGlance]. <br>
</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">Electron Microscopy, [[Resolution|Resolution]] 4.1&#8491;</td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=ANP:PHOSPHOAMINOPHOSPHONIC+ACID-ADENYLATE+ESTER'>ANP</scene>, <scene name='pdbligand=GDP:GUANOSINE-5-DIPHOSPHATE'>GDP</scene>, <scene name='pdbligand=GNP:PHOSPHOAMINOPHOSPHONIC+ACID-GUANYLATE+ESTER'>GNP</scene>, <scene name='pdbligand=MG:MAGNESIUM+ION'>MG</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=8vh4 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=8vh4 OCA], [https://pdbe.org/8vh4 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=8vh4 RCSB], [https://www.ebi.ac.uk/pdbsum/8vh4 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=8vh4 ProSAT]</span></td></tr>
</table>
== Disease ==
[https://www.uniprot.org/uniprot/LRRK2_HUMAN LRRK2_HUMAN] Defects in LRRK2 are the cause of Parkinson disease type 8 (PARK8) [MIM:[https://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> 
== Function ==
[https://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> 
<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
The leucine-rich repeat kinase 2 (LRRK2) phosphorylates a subset of RAB GTPases, and their phosphorylation levels are elevated by Parkinson's disease (PD)-linked mutations of LRRK2. However, the precise function of the LRRK2-regulated RAB GTPase in the brain remains to be elucidated. Here, we identify RAB12 as a robust LRRK2 substrate in the mouse brain through phosphoproteomics profiling and solve the structure of RAB12-LRRK2 protein complex through Cryo-EM analysis. Mechanistically, RAB12 cooperates with LRRK2 to inhibit primary ciliogenesis and regulate centrosome homeostasis in astrocytes through enhancing the phosphorylation of RAB10 and recruiting RILPL1, while the functions of RAB12 require a direct interaction with LRRK2 and LRRK2 activity. Furthermore, the ciliary and centrosome defects caused by the PD-linked LRRK2-G2019S mutation are prevented by Rab12 deletion in astrocytes. Thus, our study reveals a physiological function of the RAB12-LRRK2 complex in regulating ciliogenesis and centrosome homeostasis. The RAB12-LRRK2 structure offers a guidance in the therapeutic development of PD by targeting the RAB12-LRRK2 interaction.

RAB12-LRRK2 complex suppresses primary ciliogenesis and regulates centrosome homeostasis in astrocytes.,Li X, Zhu H, Huang BT, Li X, Kim H, Tan H, Zhang Y, Choi I, Peng J, Xu P, Sun J, Yue Z Nat Commun. 2024 Sep 29;15(1):8434. doi: 10.1038/s41467-024-52723-6. PMID:39343966<ref>PMID:39343966</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 8vh4" style="background-color:#fffaf0;"></div>
== References ==
<references/>
__TOC__
</StructureSection>
[[Category: Homo sapiens]]
[[Category: Large Structures]]
[[Category: Sun J]]
[[Category: Zhu H]]