biostudies-literatureStormo AEDNIA NIH HHSNCRR NIH HHSLaurel EndowmentFondo di Ateneo per la RicercaUCSF Parnassus Flow Cytometry CoreNational Institutes of HealthFondazione Banco di SardegnaStowers Family Endowed Chair for Dental & Mineralized Tissue ResearchNEI NIH HHSNIDDK NIH HHSDoDNINDS NIH HHSNCI NIH HHSAmerican Federation for Aging ResearchDRC CenterTaube Koret CenterMichael J Fox FoundationNIH HHSe202010065https://www.ebi.ac.uk/biostudies/studies/S-EPMC8919618biostudies-literatureUnknown221(4)Missense mutations in leucine-rich repeat kinase 2 (LRRK2) are the most common cause of familial Parkinson's disease (PD); however, pathways regulating LRRK2 subcellular localization, function, and turnover are not fully defined. We performed quantitative mass spectrometry-based interactome studies to identify 48 novel LRRK2 interactors, including the microtubule-associated E3 ubiquitin ligase TRIM1 (tripartite motif family 1). TRIM1 recruits LRRK2 to the microtubule cytoskeleton for ubiquitination and proteasomal degradation by binding LRRK2911-919, a nine amino acid segment within a flexible interdomain region (LRRK2853-981), which we designate the "regulatory loop" (RL). Phosphorylation of LRRK2 Ser910/Ser935 within LRRK2 RL influences LRRK2's association with cytoplasmic 14-3-3 versus The Journal of cell biologyThe E3 ligase TRIM1 ubiquitinates LRRK2 and controls its localization, degradation, and toxicity.PMC8919618SCR_018206R01 EY027810P30 DK063720R01 CA219815K08NS090633R01 NS107480S10 RR026758R01 NS124848RF1 AG058476K08 NS0906332014.0489R01CA219815RF1 NS124848P01 AG054407R01EY027810W81XWH-18-1-0376NIG P30 DK063720Earley EMCox TCSkibinski Gvan Haren JVon Dollen JFitzGibbon MDauer WTLum LSFinkbeiner SHiniker AWittmann TCrosio CAhrendt HJohnson JRStormo AEDShavarebi FKrogan NJDavis EJMirescu CPorath JVerschueren EIaccarino COakes SASwaney DLRavisankar ABalen CNichols RJfalseThe E3 ligase TRIM1 ubiquitinates LRRK2 and controls its localization, degradation, and toxicity.Missense mutations in leucine-rich repeat kinase 2 (LRRK2) are the most common cause of familial Parkinson's disease (PD); however, pathways regulating LRRK2 subcellular localization, function, and turnover are not fully defined. We performed quantitative mass spectrometry-based interactome studies to identify 48 novel LRRK2 interactors, including the microtubule-associated E3 ubiquitin ligase TRIM1 (tripartite motif family 1). TRIM1 recruits LRRK2 to the microtubule cytoskeleton for ubiquitination and proteasomal degradation by binding LRRK2911-919, a nine amino acid segment within a flexible interdomain region (LRRK2853-981), which we designate the "regulatory loop" (RL). Phosphorylation of LRRK2 Ser910/Ser935 within LRRK2 RL influences LRRK2's association with cytoplasmic 14-3-3 versus 2022-01-01T00:00:00Z2022 Apr2026-05-31T05:00:55.991Z2025-02-19T01:53:42.02ZS-EPMC89196183526695410.1083/jcb.202010065