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Structure and regulation of full-length human leucine-rich repeat kinase 1
Open accessPreprint — published as 10.1038/s41467-023-40532-2 · Paper page
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, with both implicated in human disease. Despite recent experimentally determined structures of LRRK2, the structure and exact molecular mechanisms regulating the activity of the LRRK1, and 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 which serve to control kinase activity, which are further validated experimentally. Both the LRRK1 monomer and dimer are structurally distinct compared to LRRK2, implying functional differences in both proteins. Overall, our results provide new structural insights into the activation of the human LRRKs for understanding the physiology and pathology of these proteins.
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Highly accurate protein structure prediction with AlphaFold
Jumper, J., Evans, R., Pritzel, A., Green, T., Figurnov, M., Ronneberger, O., Tunyasuvunakool, K., Bates, R., Žídek, A., Potapenko, A., et al. (2021) · Nature · doi:10.1038/s41586-021-03819-2 · Cited by 43,764
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Research works printed but not linked: 59
- 10.1126/science.1075762 · DOI · Paper page
- 10.1016/j.neuron.2004.11.005 · DOI
- 10.1016/j.neuron.2004.10.023 · DOI
- 10.1124/jpet.115.227587 · DOI
- 10.1126/scitranslmed.abj2658 · DOI
- 10.7554/elife.12813 · DOI · Paper page
- 10.1101/2020.11.25.397836 · DOI
- 10.1111/jnc.12798 · DOI
- 10.1242/jcs.228809 · DOI
- Fujita, K. , Kedashiro, S. , Yagi, T. & Hisamoto, N. The ULK complex – LRRK1 axis regulates Parkin-mediated mitophagy via Rab7 Ser-72 phosphorylation. Journal of Cell Science in press(2022). · DOI
- 10.1128/MCB.00085-15 · DOI
- 10.1038/ncomms1161 · DOI
- 10.1091/mbc.E11-09-0780 · DOI
- 10.1038/boneres.2017.3 · DOI
- 10.1002/jbmr.1935 · DOI
- 10.1016/j.ejmg.2021.104383 · DOI
- 10.1111/ahg.12352 · DOI
- 10.1002/jbmr.3995 · DOI
- 10.1359/jbmr.071013 · DOI
- 10.1152/ajpendo.00189.2016 · DOI
- 10.1073/pnas.1523708113 · DOI
- 10.1038/s41598-017-09126-z · DOI
- 10.1096/fj.08-111310 · DOI
- 10.1007/s00239-008-9122-4 · DOI
- 10.1016/j.cellsig.2005.08.015 · DOI
- 10.1371/journal.pone.0023207 · DOI
- 10.1074/jbc.M708718200 · DOI
- 10.1021/bi061960m · DOI
- 10.1371/journal.pone.0043472 · DOI
- 10.1038/s41586-020-2673-2 · DOI
- 10.1016/j.cell.2021.05.004 · DOI
- 10.1038/s41594-022-00863-y · DOI · Paper page
- Zhu, H. , Tonelli, F. , Alessi, D. R. & Sun, J. Structural basis of human LRRK2 membrane recruitment and activation. bioRxiv, 2022.2004.2026.489605 (2022). · DOI · Paper page
- 10.1126/science.aar5839 · DOI
- 10.1126/science.1062023 · DOI · Paper page
- 10.1371/journal.pbio.1001680 · DOI
- 10.1021/jp301628r · DOI
- 10.1016/S0092-8674(02)00741-9 · DOI
- 10.1016/j.jbc.2021.100746 · DOI
- 10.1371/journal.pbio.3001677 · DOI
- 10.1042/bcj20220308 · DOI · Paper page
- 10.1007/s00401-021-02325-z · DOI
- 10.1042/bcj20220161 · DOI · Paper page
- 10.7554/eLife.36861 · DOI
- 10.1016/j.jsb.2021.107702 · DOI
- 10.1186/s12934-016-0600-x · DOI
- 10.1038/nmeth.2019 · DOI · Paper page
- 10.1038/nmeth.4169 · DOI · Paper page
- 10.1038/s41592-019-0575-8 · DOI
- 10.1038/s41467-020-18952-1 · DOI
- 10.1038/s41592-020-00990-8 · DOI
- 10.1107/S2059798319011471 · DOI · Paper page
- 10.1093/nar/gkab1061 · DOI · Paper page
- 10.1002/jcc.20084 · DOI
- 10.1101/249607 · DOI
- 10.1107/S0907444910007493 · DOI · Paper page
- 10.1002/pro.3330 · DOI · Paper page
- 10.1002/pro.3943 · DOI
- 10.1002/pro.3235 · DOI · Paper page
Metadata
- Authors
- Metcalfe, R. D., Fiesco, J. A. M., & Zhang, P.
- Affiliations
- National Cancer Institute (US)
- Frederick National Laboratory for Cancer Research (US)
- Corresponding author
- Zhang, P.
- Venue
- Nature Communications
- Publisher
- openRxiv
- Published
- 2022-12-23
- Volume
- 14
- Issue
- 1
- Pages
- 4797-4797
- ISSN
- 2041-1723 (ISSN-L)
- PMC
- PMC10412621
- OpenAlex
- W4385700141
- Cited by
- 8
- References
- 1
- Citations by year
- 2026: 2 · 2025: 4 · 2024: 2
- FWCI
- 0.71
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- cc-by
- 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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