Structure and regulation of full-length human leucine-rich repeat kinase 1

FARE Award Winner

Authors

• G Salem
• M Garmendia-Cedillos
• A Somenhalli
• N Khandekar
• L Argueta
• N Cubert
• I Farooq
• M Jaime
• T Kaufman
• J Holsopple
• S Smoot
• T Kaufman
• J Tennessen
• B Oliver
• T Pohida

Abstract

The two human leucine-rich repeat kinases (LRRKs), LRRK1 and LRRK2 are large and unusually complex multi-domain kinases which serve to regulate fundamental cellular processes. Near-uniquely, the LRRKs contain both a kinase domain and Ras-like GTPase domain in the same polypeptide chain, along with several scaffolding domains. Both LRRKs are implicated in human disease. Specifically, LRRK1 is implicated in bone development, with mutations in LRRK1 causing a bone disease, osteosclerotic metaphyseal dysplasia (OSMD), while mutations in LRRK2 are associated with Parkinson’s disease. Despite their biological significance, both LRRKs have proved to be challenging structural targets, due to their size (~250 kDa), heterogeneity, flexibility, and low recombinant expression levels. Recent experimental structures of LRRK2 in a variety of states have begun to provide structural detail into this family of proteins, however the structure and exact molecular mechanisms regulating the activity of LRRK1 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 which serve to control kinase activity through linking the kinase domain and the Ras-like GTPase domain, which we have further validated experimentally. LRRK1 is structurally distinct compared to LRRK2, particularly in the position of the leucine-rich repeats relative to the kinase domain. Overall, our results provide new structural insights into the human LRRKs for understanding the physiology and pathology of these proteins.

A preprint is available describing these results: doi.org/10.1101/2022.12.21.521433.

Scientific Focus Area: Structural Biology

This page was last updated on Monday, September 25, 2023