{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,11]],"date-time":"2026-09-11T04:51:28Z","timestamp":1789102288250,"version":"build-2803163510"},"reference-count":36,"publisher":"Oxford University Press (OUP)","issue":"4","license":[{"start":{"date-parts":[[2026,4,9]],"date-time":"2026-04-09T00:00:00Z","timestamp":1775692800000},"content-version":"vor","delay-in-days":8,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"funder":[{"DOI":"10.13039\/100006132","name":"Department of Energy (DOE) Office of Science","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100006132","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100006224","name":"Argonne National Laboratory","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100006224","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2026,4,7]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Mutations in leucine-rich repeat kinase 2 (LRRK2) are the most common cause of familial Parkinson\u2019s disease, yet the molecular mechanism governing LRRK2 activation remains incompletely understood. LRRK2 is a large multidomain enzyme whose kinase activity is regulated by intramolecular interactions and by its Ras of complex proteins (ROC) GTPase domain. Here, we combine cryo\u2013electron microscopy, X-ray crystallography, and structure-guided biochemical perturbations to define how ROC conformational switching regulates LRRK2 activation. Cryo-EM reconstructions reveal that monomeric full-length LRRK2 samples three distinct conformational states\u2014autoinhibited, intermediate, and activated\u2014indicating that large-scale activation-associated rearrangements can occur through an intrinsic intramolecular pathway, independently of Rab29 binding, higher-order oligomerization, or membrane association. A 1.6-\u00c5 crystal structure of an extended ROC construct reveals intrinsic conformational plasticity within the GTPase switch regions that likely underlies these transitions. Structure-guided disulfide engineering identifies a functional coupling between residue R1441 and switch II that directly modulates GTPase activity in both isolated ROC and full-length LRRK2. Disruption of this coupling phenocopies the disease-associated R1441H mutation. Together, these findings establish ROC as a dynamic conformational engine that drives a multistep intramolecular activation mechanism in LRRK2, providing mechanistic insight into how pathogenic mutations promote aberrant kinase activation.<\/jats:p>","DOI":"10.1093\/pnasnexus\/pgag112","type":"journal-article","created":{"date-parts":[[2026,4,12]],"date-time":"2026-04-12T16:52:50Z","timestamp":1776012770000},"source":"Crossref","is-referenced-by-count":1,"title":["Structural and biochemical basis of ROC-dependent activation of LRRK2"],"prefix":"10.1093","volume":"5","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-0867-7529","authenticated-orcid":false,"given":"Yangshin","family":"Park","sequence":"first","affiliation":[{"name":"Department of Biochemistry, Molecular Biology, and Pharmacology, Indiana University School of Medicine , Indianapolis, IN 46202, USA"},{"name":"The Stark Neurosciences Research Institute, Indiana University School of Medicine , Indianapolis, IN 46202, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chunxiang","family":"Wu","sequence":"additional","affiliation":[{"name":"Department of Biochemistry, Molecular Biology, and Pharmacology, Indiana University School of Medicine , Indianapolis, IN 46202, USA"},{"name":"The Stark Neurosciences Research Institute, Indiana University School of Medicine , Indianapolis, IN 46202, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0009-0832-4003","authenticated-orcid":false,"given":"Kayla","family":"Tennessen","sequence":"additional","affiliation":[{"name":"Department of Biochemistry, Molecular Biology, and Pharmacology, Indiana University School of Medicine , Indianapolis, IN 46202, USA"},{"name":"The Stark Neurosciences Research Institute, Indiana University School of Medicine , Indianapolis, IN 46202, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5266-9329","authenticated-orcid":false,"given":"Li","family":"Wan","sequence":"additional","affiliation":[{"name":"Department of Biochemistry, Molecular Biology, and Pharmacology, Indiana University School of Medicine , Indianapolis, IN 46202, USA"},{"name":"The Stark Neurosciences Research Institute, Indiana University School of Medicine , Indianapolis, IN 46202, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Neo C","family":"Hoang","sequence":"additional","affiliation":[{"name":"Department of Biochemistry, Molecular Biology, and Pharmacology, Indiana University School of Medicine , Indianapolis, IN 46202, USA"},{"name":"The Stark Neurosciences Research Institute, Indiana University School of Medicine , Indianapolis, IN 46202, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0007-7876-3947","authenticated-orcid":false,"given":"Cardea W","family":"Hoang","sequence":"additional","affiliation":[{"name":"Department of Biochemistry, Molecular Biology, and Pharmacology, Indiana University School of Medicine , Indianapolis, IN 46202, USA"},{"name":"The Stark Neurosciences Research Institute, Indiana University School of Medicine , Indianapolis, IN 46202, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jingling","family":"Liao","sequence":"additional","affiliation":[{"name":"Department of Biochemistry, Molecular Biology, and Pharmacology, Indiana University School of Medicine , Indianapolis, IN 46202, USA"},{"name":"The Stark Neurosciences Research Institute, Indiana University School of Medicine , Indianapolis, IN 46202, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6346-736X","authenticated-orcid":false,"given":"Quyen Q","family":"Hoang","sequence":"additional","affiliation":[{"name":"Department of Biochemistry, Molecular Biology, and Pharmacology, Indiana University School of Medicine , Indianapolis, IN 46202, USA"},{"name":"The Stark Neurosciences Research Institute, Indiana University School of Medicine , Indianapolis, IN 46202, USA"},{"name":"Department of Neurology, Indiana University School of Medicine , Indianapolis, IN 46202, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2026,4,9]]},"reference":[{"key":"2026042213085886500_pgag112-B1","doi-asserted-by":"crossref","first-page":"1229","DOI":"10.1016\/S0140-6736(05)74809-1","article-title":"LRRK2 mutations and Parkinsonism","volume":"365","author":"Toft","year":"2005","journal-title":"Lancet"},{"key":"2026042213085886500_pgag112-B2","doi-asserted-by":"crossref","first-page":"601","DOI":"10.1016\/j.neuron.2004.11.005","article-title":"Mutations in LRRK2 cause autosomal-dominant parkinsonism with pleomorphic pathology","volume":"44","author":"Zimprich","year":"2004","journal-title":"Neuron"},{"key":"2026042213085886500_pgag112-B3","doi-asserted-by":"crossref","first-page":"3549","DOI":"10.1093\/hmg\/ddi376","article-title":"Comprehensive evaluation of common genetic variation within LRRK2 reveals evidence for association with sporadic Parkinson\u2019s disease","volume":"14","author":"Skipper","year":"2005","journal-title":"Hum Mol Genet"},{"key":"2026042213085886500_pgag112-B4","doi-asserted-by":"crossref","first-page":"4074","DOI":"10.3390\/ijms19124074","article-title":"Roco proteins and the Parkinson\u2019s disease-associated LRRK2","volume":"19","author":"Liao","year":"2018","journal-title":"Int J Mol Sci"},{"key":"2026042213085886500_pgag112-B5","doi-asserted-by":"crossref","first-page":"3519","DOI":"10.1016\/j.cell.2021.05.004","article-title":"Structural analysis of the full-length human LRRK2","volume":"184","author":"Myasnikov","year":"2021","journal-title":"Cell"},{"key":"2026042213085886500_pgag112-B6","doi-asserted-by":"crossref","first-page":"1038","DOI":"10.1016\/j.tibs.2022.06.009","article-title":"Roc, the G-domain of the Parkinson\u2019s disease-associated protein LRRK2","volume":"47","author":"Park","year":"2022","journal-title":"Trends Biochem Sci"},{"key":"2026042213085886500_pgag112-B7","doi-asserted-by":"crossref","first-page":"110376","DOI":"10.1016\/j.jbc.2025.110376","article-title":"Structural biology of Parkinson\u2019s disease-associated leucine-rich repeat kinase 2 (LRRK2)","volume":"301","author":"Leschziner","year":"2025","journal-title":"J Biol 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