View source for 9ci3


==Structure of the LRRK2/14-3-3 complex==
<StructureSection load='9ci3' size='340' side='right'caption='[[9ci3]], [[Resolution|resolution]] 3.96&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[9ci3]] is a 3 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=9CI3 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=9CI3 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]] 3.96&#8491;</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=SEP:PHOSPHOSERINE'>SEP</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=9ci3 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=9ci3 OCA], [https://pdbe.org/9ci3 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=9ci3 RCSB], [https://www.ebi.ac.uk/pdbsum/9ci3 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=9ci3 ProSAT]</span></td></tr>
</table>
== Function ==
[https://www.uniprot.org/uniprot/1433G_HUMAN 1433G_HUMAN] Adapter protein implicated in the regulation of a large spectrum of both general and specialized signaling pathways. Binds to a large number of partners, usually by recognition of a phosphoserine or phosphothreonine motif. Binding generally results in the modulation of the activity of the binding partner.<ref>PMID:16511572</ref> 
<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
Leucine-rich repeat kinase 2 (LRRK2) is an essential regulator in cellular signaling and a major contributor to Parkinson's disease (PD) pathogenesis. 14-3-3 proteins are critical modulators of LRRK2 activity, yet the structural basis of their interaction has remained unclear. Here, we present the cryo-electron microscopy structure of the LRRK2:14-3-3(2) autoinhibitory complex, revealing how a 14-3-3 dimer stabilizes an autoinhibited LRRK2 monomer through dual-site anchoring. The dimer engages both phosphorylated S910/S935 sites and the COR-A/B subdomains within the Roc-COR GTPase region. This spatial configuration constrains LRR domain mobility, reinforces the inactive conformation, and likely impedes LRRK2 dimerization and oligomer formation. Structure-guided mutagenesis studies show that PD-associated mutations at the COR:14-3-3(2) interface and within the GTPase domain weaken 14-3-3 binding and impair its inhibitory effect on LRRK2 kinase activity. Furthermore, we demonstrate that type I LRRK2 kinase inhibitor, which stabilizes the kinase domain in its active conformation, reduces 14-3-3 binding and promotes dephosphorylation at pS910 and pS935. Together, these findings provide a structural basis for understanding how LRRK2 is maintained in an inactive state, elucidate the mechanistic role of 14-3-3 in LRRK2 regulation, inform the interpretation of PD biomarkers, and suggest therapeutic strategies aimed at enhancing LRRK2-14-3-3 interactions to treat PD and related disorders.

14-3-3 binding maintains the Parkinson's associated kinase LRRK2 in an inactive state.,Martinez Fiesco JA, Beilina A, Alvarez de la Cruz A, Li N, Metcalfe RD, Cookson MR, Zhang P Nat Commun. 2025 Aug 5;16(1):7226. doi: 10.1038/s41467-025-62337-1. PMID:40764514<ref>PMID:40764514</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 9ci3" style="background-color:#fffaf0;"></div>
== References ==
<references/>
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</StructureSection>
[[Category: Homo sapiens]]
[[Category: Large Structures]]
[[Category: Martinez Fiesco JA]]
[[Category: Zhang P]]