Structural basis for Parkinson’s disease-linked LRRK2’s binding to microtubules
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Abstract
Leucine-rich repeat kinase 2 ( LRRK2 ) is one of the most commonly mutated genes in familial Parkinson’s disease (PD). Under some circumstances, LRRK2 co-localizes with microtubules in cells, an association enhanced by PD mutations. We report a cryo-EM structure of the catalytic half of LRRK2, containing its kinase, in a closed conformation, and GTPase domains, bound to microtubules. We also report a structure of the catalytic half of LRRK1, which is closely related to LRRK2 but is not linked to PD. Although LRRK1’s structure is similar to that of LRRK2, we find that LRRK1 does not interact with microtubules. Guided by these structures, we identify amino acids in LRRK2’s GTPase that mediate microtubule binding; mutating them disrupts microtubule binding in vitro and in cells, without affecting LRRK2’s kinase activity. Our results have implications for the design of therapeutic LRRK2 kinase inhibitors.
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Cites
Highly accurate protein structure prediction with AlphaFold
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“and pET17b-Kif5b(1-560)-GFP-His61 was obtained from Addgene (#15219).”
LRRK2 levels in immune cells are increased in Parkinson’s disease
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- Authors
- Snead, D. M., Matyszewski, M., Dickey, A. M., Lin, Y. X., Leschziner, A. E., & Reck-Peterson, S. L.
- Affiliations
- Johns Hopkins University (US)
- University of California San Diego (US)
- ORCID
- Venue
- Nature Structural & Molecular Biology
- Published
- 2022-12
- Volume
- 29
- Issue
- 12
- Pages
- 1196-1207
- ISSN
- 1545-9985 (ISSN-L)
- 1545-9993
- PMC
- PMC9758056
- OpenAlex
- W4311901922
- Cited by
- 54
- References
- 4
- Citations by year
- 2026: 12 · 2025: 12 · 2024: 16 · 2023: 11 · 2022: 3
- FWCI
- 5.53
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Nature Structural & Molecular Biology (publishedVersion, cc-by)
- bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by-nc-nd)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Funders
- Howard Hughes Medical Institute
- Michael J. Fox Foundation for Parkinson's Research
- A.P. Giannini Foundation
- Giannini Foundation of Agricultural Economics
- National Institutes of Health
- University of California, San Diego
- National Institute of General Medical Sciences (R01GM107214, T32GM007198, T32GM008326, R35GM141825)
- Topics
- Health Sciences › Medicine › Neurology › Parkinson's Disease Mechanisms and Treatments
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Kinase Regulation and GTPase Signaling
- Physical Sciences › Materials Science › Materials Chemistry › Enzyme Structure and Function
- Keywords
- LRRK2, LRRK1, Parkinson's disease, microtubule binding, GTPase domain, kinase domain, protein structure, familial Parkinson's disease mutations, LRRK2 inhibitors, cryo-EM structure
- MeSH terms
- Leucine-Rich Repeat Serine-Threonine Protein Kinase-2, Humans, Microtubules, Mutation, Parkinson Disease, GTP Phosphohydrolases
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