{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,28]],"date-time":"2026-04-28T05:40:02Z","timestamp":1777354802338,"version":"3.51.4"},"reference-count":17,"publisher":"Wiley","issue":"7","license":[{"start":{"date-parts":[[2025,6,22]],"date-time":"2025-06-22T00:00:00Z","timestamp":1750550400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100000288","name":"Royal Society","doi-asserted-by":"publisher","award":["IF\\R2\\222002"],"award-info":[{"award-number":["IF\\R2\\222002"]}],"id":[{"id":"10.13039\/501100000288","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000864","name":"Michael J. Fox Foundation for Parkinson's Research","doi-asserted-by":"publisher","award":["021184"],"award-info":[{"award-number":["021184"]}],"id":[{"id":"10.13039\/100000864","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000864","name":"Michael J. Fox Foundation for Parkinson's Research","doi-asserted-by":"publisher","award":["18285"],"award-info":[{"award-number":["18285"]}],"id":[{"id":"10.13039\/100000864","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Protein Science"],"published-print":{"date-parts":[[2025,7]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>\n                    The\n                    <jats:italic>LRRK2<\/jats:italic>\n                    gene is a key contributor to the genetic risk of Parkinson's disease, and a priority drug target for the disorder. Leucine Rich Repeat Kinase 2, the protein product of\n                    <jats:italic>LRRK2<\/jats:italic>\n                    , is a multidomain enzyme implicated in a range of cellular processes\u2014including endolysosomal trafficking and damage response. Based on the report that truncation and structural variants resulting in loss of LRRK2 protein are observed in human populations, genomic sequence repositories were queried for coding variants affecting key catalytic residues in LRRK2\u2014resulting in the identification of three variants (K1347E, K1347R, and T1348P) predicted to ablate the capacity of LRRK2 to bind GTP. Biochemical and cellular characterization of these variants confirmed loss of GTP binding, as well as reduced or loss of kinase activity. These data demonstrate the presence of rare coding enzymatic loss\u2010of\u2010function variants in humans, with implications for our understanding of LRRK2 as a driver of disease and as a drug target.\n                  <\/jats:p>","DOI":"10.1002\/pro.70190","type":"journal-article","created":{"date-parts":[[2025,6,23]],"date-time":"2025-06-23T01:05:22Z","timestamp":1750640722000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Loss\u2010of\u2010function coding variants in the Ras of complex proteins\/\n                    <scp>GTPase<\/scp>\n                    domain of leucine rich repeat kinase 2"],"prefix":"10.1002","volume":"34","author":[{"given":"Sarah","family":"Butterfield","sequence":"first","affiliation":[{"name":"Department of Comparative Biomedical Sciences Royal Veterinary College  Camden Town UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Susanne","family":"Herbst","sequence":"additional","affiliation":[{"name":"Department of Comparative Biomedical Sciences Royal Veterinary College  Camden Town UK"},{"name":"Department of Neurodegenerative disease UCL Queen Square Institute of Neurology  London UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4537-0489","authenticated-orcid":false,"given":"Patrick Alfryn","family":"Lewis","sequence":"additional","affiliation":[{"name":"Department of Comparative Biomedical Sciences Royal Veterinary College  Camden Town UK"},{"name":"Department of Neurodegenerative disease UCL Queen Square Institute of Neurology  London UK"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2025,6,22]]},"reference":[{"key":"e_1_2_7_2_1","doi-asserted-by":"publisher","DOI":"10.1146\/annurev-biochem-030122-051144"},{"key":"e_1_2_7_3_1","doi-asserted-by":"publisher","DOI":"10.1001\/jamaneurol.2018.1885"},{"key":"e_1_2_7_4_1","doi-asserted-by":"publisher","DOI":"10.1021\/bi061960m"},{"key":"e_1_2_7_5_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-020-2308-7"},{"key":"e_1_2_7_6_1","doi-asserted-by":"publisher","DOI":"10.1042\/BST20180462"},{"key":"e_1_2_7_7_1","doi-asserted-by":"publisher","DOI":"10.1126\/scitranslmed.abq7374"},{"key":"e_1_2_7_8_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbrc.2007.04.006"},{"key":"e_1_2_7_9_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(23)01478-2"},{"key":"e_1_2_7_10_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2021.05.004"},{"key":"e_1_2_7_11_1","doi-asserted-by":"publisher","DOI":"10.7554\/eLife.31012"},{"key":"e_1_2_7_12_1","doi-asserted-by":"publisher","DOI":"10.7554\/eLife.12813"},{"key":"e_1_2_7_13_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-024-07556-0"},{"key":"e_1_2_7_14_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41531-023-00544-7"},{"key":"e_1_2_7_15_1","doi-asserted-by":"publisher","DOI":"10.1126\/science.1062023"},{"key":"e_1_2_7_16_1","doi-asserted-by":"crossref","DOI":"10.1101\/cshperspect.a041774","article-title":"Genetics of Parkinson's disease: from causes to treatment","volume":"12","author":"Westenberger A","year":"2024","journal-title":"Cold Spring Harb Perspect Med"},{"key":"e_1_2_7_17_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41591-020-0893-5"},{"key":"e_1_2_7_18_1","doi-asserted-by":"publisher","DOI":"10.1242\/jcs.259724"}],"container-title":["Protein Science"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/pro.70190","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,6,27]],"date-time":"2025-06-27T02:16:03Z","timestamp":1750990563000},"score":1,"resource":{"primary":{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/10.1002\/pro.70190"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,6,22]]},"references-count":17,"journal-issue":{"issue":"7","published-print":{"date-parts":[[2025,7]]}},"alternative-id":["10.1002\/pro.70190"],"URL":"https:\/\/doi.org\/10.1002\/pro.70190","archive":["Portico"],"relation":{"has-preprint":[{"id-type":"doi","id":"10.1101\/2024.12.07.627348","asserted-by":"object"}]},"ISSN":["0961-8368","1469-896X"],"issn-type":[{"value":"0961-8368","type":"print"},{"value":"1469-896X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,6,22]]},"assertion":[{"value":"2024-12-10","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2025-05-25","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2025-06-22","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"e70190"}}