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The E3 ligase TRIM1 ubiquitinates LRRK2 and controls its localization, degradation, and toxicity [article]

Adrienne E. D. Stormo, Molly FitzGibbon, Farbod Shavarebi, Elizabeth M. Earley, Lotus S. Lum, Erik Verschueren, Danielle L. Swaney, Gaia Skibinski, Abinaya Ravisankar, Jeffrey van Haren, Emily J. Davis, Jeffrey R. Johnson (+11 others)
2020 bioRxiv   pre-print

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AbstractMissense 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
more » ... quitination and proteasomal degradation by binding LRRK2822-982, a flexible interdomain region we designate the "Regulatory Loop" (RL). Phosphorylation of LRRK2 Ser910/935 within LRRK2 RL serves as a molecular switch controlling LRRK2's association with cytoplasmic 14-3-3 versus microtubule-bound TRIM1. Association with TRIM1 prevents upregulation of LRRK2 kinase activity by Rab29 and also rescues neurite outgrowth deficits caused by PD-driving mutant LRRK2 G2019S. Our data suggest that TRIM1 is a critical regulator of LRRK2, modulating its cytoskeletal recruitment, turnover, kinase activity, and cytotoxicity.
doi:10.1101/2020.10.21.336578 fatcat:yukskgc7i5ad3brq6sx4jimcdu
Citation

Adrienne E. D. Stormo, Molly FitzGibbon, Farbod Shavarebi, Elizabeth M. Earley, Lotus S. Lum, Erik Verschueren, Danielle L. Swaney, Gaia Skibinski, Abinaya Ravisankar, Jeffrey van Haren, Emily J. Davis, Jeffrey R. Johnson, John Von Dollen, Christian Mirescu, Ciro Iaccarino, William T. Dauer, R. Jeremy Nichols, Torsten Wittmann, Timothy C. Cox, Steve Finkbeiner, Nevan J. Krogan, Scott A. Oakes, Annie Hiniker. "The E3 ligase TRIM1 ubiquitinates LRRK2 and controls its localization, degradation, and toxicity." bioRxiv (2020)