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Structure of LRRK1 and mechanisms of autoinhibition and activation
Open accessPreprint — published as 10.1038/s41594-023-01109-1
Abstract
Leucine Rich Repeat Kinase 1 and 2 (LRRK1 and LRRK2) are homologs in the ROCO family of proteins in humans. Despite their shared domain architecture and involvement in intracellular trafficking, their disease associations are strikingly different: LRRK2 is involved in familial Parkinson’s Disease (PD) while LRRK1 is linked to bone diseases. Furthermore, PD-linked mutations in LRRK2 are typically autosomal dominant gain-of-function while those in LRRK1 are autosomal recessive loss-of-function. To understand these differences, we solved cryo-EM structures of LRRK1 in its monomeric and dimeric forms. Both differ from the corresponding LRRK2 structures. Unlike LRRK2, which is sterically autoinhibited as a monomer, LRRK1 is sterically autoinhibited in a dimer-dependent manner. LRRK1 has an additional level of autoinhibition that prevents activation of the kinase and is absent in LRRK2. Finally, we place the structural signatures of LRRK1 and LRRK2 in the context of the evolution of the LRRK family of proteins.
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Highly accurate protein structure prediction with AlphaFold
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Metadata
- Authors
- Reimer, J. M., Dickey, A. M., Lin, Y. X., Abrisch, R. G., Mathea, S., Chatterjee, D., Fay, E. J., Knapp, S., Daugherty, M. D., Reck-Peterson, S. L., & Leschziner, A. E.
- Affiliations
- University of California San Diego (US)
- Goethe University Frankfurt (DE)
- ORCID
- Venue
- Nature Structural & Molecular Biology
- Publisher
- openRxiv
- Published
- 2022-11-23
- Volume
- 30
- Issue
- 11
- Pages
- 1735-1745
- ISSN
- 1545-9985 (ISSN-L)
- PMC
- PMC10643122
- OpenAlex
- W4387782462
- Cited by
- 15
- References
- 1
- Citations by year
- 2026: 4 · 2025: 8 · 2024: 1 · 2023: 2
- FWCI
- 1.34
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- cc-by
- Locations
- Nature Structural & Molecular Biology (publishedVersion, cc-by)
- bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- eScholarship (California Digital Library) (submittedVersion, cc-by)
- Funders
- Michael J. Fox Foundation for Parkinson's Research
- National Institutes of Health
- University of California, San Diego
- Medical Research Council
- National Heart, Lung, and Blood Institute
- National Institute of Mental Health
- NIH Office of the Director
- National Cancer Institute
- National Institute of General Medical Sciences (R35GM133633)
- Common Fund
- 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, protein dimerization, autoinhibition, kinase activation, cryo-EM structure, Parkinson's disease, bone disease, gain-of-function mutations, loss-of-function mutations, protein evolution, intracellular trafficking
- MeSH terms
- Humans, Mutation, Parkinson Disease, Proteins, Protein Serine-Threonine Kinases
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