{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,10,7]],"date-time":"2026-10-07T16:09:17Z","timestamp":1791389357090,"version":"4.3.3"},"posted":{"date-parts":[[2026,5,5]]},"group-title":"Biochemistry","reference-count":74,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2026,5,5]],"date-time":"2026-05-05T00:00:00Z","timestamp":1777939200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"funder":[{"id":[{"id":"https:\/\/ror.org\/03rx10x31","id-type":"ROR","asserted-by":"publisher"}]},{"award":["R01NS129795"],"award-info":[{"award-number":["R01NS129795"]}],"id":[{"id":"https:\/\/ror.org\/01s5ya894","id-type":"ROR","asserted-by":"publisher"}]},{"name":"Medical Research Council","award":["MC_UU_00018\/1"],"award-info":[{"award-number":["MC_UU_00018\/1"]}]},{"name":"President Young Professorship"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2026,5,5]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                <jats:p>\n                  Gain-of-function mutations in\n                  <jats:italic>LRRK2<\/jats:italic>\n                  are a major cause of inherited Parkinson\u2019s disease.\n                  <jats:italic>LRRK2<\/jats:italic>\n                  encodes a multidomain kinase, whose bidirectional interplay with Rab GTPases regulates critical cellular processes like lysosomal homeostasis. Certain Rabs, including Rab12 and Rab29, recruit LRRK2 to organelle membranes and stimulate its kinase activity; activated LRRK2 phosphorylates a subset of Rabs in their Switch-II motifs. Molecular basis governing selective Rab recognition by LRRK2 remains unclear. Here we structurally characterize LRRK2 interactions with representative Rab GTPases and identify three novel Rab-binding sites: site 4 for Rab8A\/10, site 5 for Rab43, and site 6 for Rab5A, defining a total of six distinct binding sites that account for known LRRK2-interacting Rabs. Additionally, we elucidated the binding site of GABARAP, an ATG8 member that recruits LRRK2 to stressed lysosomes. Our findings provide a framework for therapeutic targeting of LRRK2 recruitment for Parkinson\u2019s.\n                <\/jats:p>","DOI":"10.64898\/2026.04.30.722110","type":"posted-content","created":{"date-parts":[[2026,5,5]],"date-time":"2026-05-05T21:35:14Z","timestamp":1778016914000},"source":"Crossref","is-referenced-by-count":1,"title":["Elucidating the molecular interplay between LRRK2 and Rab GTPases"],"prefix":"10.64898","author":[{"given":"Hanwen","family":"Zhu","sequence":"first","affiliation":[{"name":"Department of Structural Biology, St. Jude Children\u2019s Research Hospital, Memphis, TN, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Liam","family":"Eade","sequence":"additional","affiliation":[{"name":"MRC Protein Phosphorylation and Ubiquitylation Unit, School of Life Sciences, University of Dundee, Dundee DD1 5EH, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dario R.","family":"Alessi","sequence":"additional","affiliation":[{"name":"MRC Protein Phosphorylation and Ubiquitylation Unit, School of Life Sciences, University of Dundee, Dundee DD1 5EH, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ji","family":"Sun","sequence":"additional","affiliation":[{"name":"Department of Structural Biology, St. Jude Children\u2019s Research Hospital, Memphis, TN, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"54368","reference":[{"key":"2026050711350815000_2026.04.30.722110v1.1","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(09)60492-X"},{"key":"2026050711350815000_2026.04.30.722110v1.2","doi-asserted-by":"publisher","DOI":"10.1038\/s41582-019-0301-2"},{"key":"2026050711350815000_2026.04.30.722110v1.3","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuron.2004.10.023"},{"key":"2026050711350815000_2026.04.30.722110v1.4","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuron.2004.11.005"},{"key":"2026050711350815000_2026.04.30.722110v1.5","doi-asserted-by":"publisher","DOI":"10.1042\/bcj20220161"},{"key":"2026050711350815000_2026.04.30.722110v1.6","doi-asserted-by":"publisher","DOI":"10.2174\/1389203717666160311121748"},{"key":"2026050711350815000_2026.04.30.722110v1.7","doi-asserted-by":"crossref","first-page":"454","DOI":"10.1093\/hmg\/ddab058","article-title":"Identification of LRRK2 missense variants in the accelerating medicines partnership Parkinson\u2019s disease cohort","volume":"30","year":"2021","journal-title":"Hum. 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NPJ Parkinsons Dis. 9, 104 (2023).","DOI":"10.1038\/s41531-023-00544-7"},{"key":"2026050711350815000_2026.04.30.722110v1.12","doi-asserted-by":"crossref","unstructured":"Alessi, D.R. & Pfeffer, S.R. Leucine-rich repeat kinases. Ann. Rev. Biochem. (2024).","DOI":"10.1146\/annurev-biochem-030122-051144"},{"key":"2026050711350815000_2026.04.30.722110v1.13","doi-asserted-by":"crossref","unstructured":"Leschziner, A.E . Structural biology of Parkinson\u2019s Disease-associated leucine-rich repeat kinase 2 (LRRK2). J. Biol. Chem, 110376 (2025).","DOI":"10.1016\/j.jbc.2025.110376"},{"key":"2026050711350815000_2026.04.30.722110v1.14","doi-asserted-by":"crossref","first-page":"6871","DOI":"10.1111\/febs.16099","article-title":"LRRK2 recruitment, activity, and function in organelles","volume":"289","year":"2022","journal-title":"FEBS J"},{"key":"2026050711350815000_2026.04.30.722110v1.15","doi-asserted-by":"crossref","unstructured":"Usmani, A. , Shavarebi, F. & Hiniker, A . 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