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Cited by 8Protein Kinase Regulation and GTPase SignalingParkinson's Disease Mechanisms and TreatmentsEnzyme Structure and Function

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

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Metcalfe, Riley D., Martinez Fiesco, Juliana A., Bonet-Ponce, Luis, Kluss, Jillian H., Cookson, Mark R., Zhang, Ping·2023·Nature Communications
DOI 10.1038/s41467-023-40532-2PMC PMC10412621

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Abstract

The 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.

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Metadata

Authors
Metcalfe, R. D., Martinez Fiesco, J. A., Bonet-Ponce, L., Kluss, J. H., Cookson, M. R., & Zhang, P.
Affiliations
  • National Cancer Institute (US)
  • National Institutes of Health (US)
  • Frederick National Laboratory for Cancer Research (US)
Corresponding author
Zhang, Ping
ORCID
Venue
Nature Communications
Publisher
Springer Science and Business Media LLC
Published
2023-08-09
Volume
14
Issue
1
Pages
4797-4797
ISSN
2041-1723 (ISSN-L)
DOI
10.1038/s41467-023-40532-2
PMC
PMC10412621
OpenAlex
W4385700141
Cited by
8
References
2
Citations by year
2026: 2 · 2025: 4 · 2024: 2
FWCI
0.71
Type
journal article
Language
en
Open access
Licence
Locations
  • Nature Communications (publishedVersion, cc-by)
  • bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • RePEc: Research Papers in Economics (submittedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
  • National Institutes of Health
  • National Institute on Aging
  • National Cancer Institute (ZIABC011744)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Kinase Regulation and GTPase Signaling
  • Health Sciences › Medicine › Clinical Neurology › Parkinson's Disease Mechanisms and Treatments
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Structural Biology › Enzyme Structure and Function
Keywords
LRRK1, LRRK2, kinase activation, inactive kinase conformation, interdomain interface, cryo-EM structure, kinase regulation, protein structure
MeSH terms
Humans, Leucine, Phosphorylation, Protein Serine-Threonine Kinases

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