8fac
Structure of the leucine-rich repeat kinase 1 monomerStructure of the leucine-rich repeat kinase 1 monomer
Structural highlights
DiseaseLRRK1_HUMAN Osteosclerotic metaphyseal dysplasia. The disease is caused by variants affecting the gene represented in this entry. FunctionLRRK1_HUMAN Plays a role in the negative regulation of bone mass, acting through the maturation of osteoclasts.[UniProtKB:Q3UHC2] Publication Abstract from PubMedThe human leucine-rich repeat kinases (LRRKs), LRRK1 and LRRK2 are large and unusually complex multi-domain kinases, which regulate fundamental cellular processes and have been implicated in human disease. Structures of LRRK2 have recently been determined, but the structure and molecular mechanisms regulating the activity of the LRRK1 as well as differences in the regulation of LRRK1 and LRRK2 remain unclear. Here, we report a cryo-EM structure of the LRRK1 monomer and a lower-resolution cryo-EM map of the LRRK1 dimer. The monomer structure, in which the kinase is in an inactive conformation, reveals key interdomain interfaces that control kinase activity as we validate experimentally. Both the LRRK1 monomer and dimer are structurally distinct compared to LRRK2. Overall, our results provide structural insights into the activation of the human LRRKs, which advance our understanding of their physiological and pathological roles. Structure and regulation of full-length human leucine-rich repeat kinase 1.,Metcalfe RD, Martinez Fiesco JA, Bonet-Ponce L, Kluss JH, Cookson MR, Zhang P Nat Commun. 2023 Aug 9;14(1):4797. doi: 10.1038/s41467-023-40532-2. PMID:37558661[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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