Activation of parkin by a molecular glue
Mutations in parkin and PINK1 cause early-onset Parkinson's disease (EOPD). The ubiquitin ligase parkin is recruited to damaged mitochondria and activated by PINK1, a kinase that phosphorylates ubiquitin and the ubiquitin-like domain of parkin. Activated phospho-parkin then ubiquitinates mitochondrial proteins to target the damaged organelle for degradation. Here, we present the mechanism of activation of a new class of small molecule allosteric modulators that enhance parkin activity. The compounds act as molecular glues to enhance the ability of phospho-ubiquitin (pUb) to activate parkin. Ubiquitination assays and isothermal titration calorimetry with the most active compound (BIO-2007817) identify the mechanism of action. We present the crystal structure of a closely related compound (BIO-1975900) bound to a complex of parkin and two pUb molecules. The compound binds next to pUb on RING0 and contacts both proteins. Hydrogen-deuterium exchange mass spectrometry (HDX-MS) experiments confirm that activation occurs through release of the catalytic Rcat domain. In organello and mitophagy assays demonstrate that BIO-2007817 partially rescues the activity of parkin EOPD mutants, R42P and V56E, offering a basis for the design of activators as therapeutics for Parkinson's disease.
Authors
- Laura Silvian (ORCID: https://orcid.org/0000-0002-5299-5201)
- Nathalie Croteau
- Kalle Gehring (ORCID: https://orcid.org/0000-0001-6500-1184)
- Nupur Bansal (ORCID: https://orcid.org/0000-0003-3226-330X)
- Warren D. Hirst (ORCID: https://orcid.org/0000-0003-0389-8891)
- Jean‐François Trempe (ORCID: https://orcid.org/0000-0002-6543-3371)
- Edward A. Fon (ORCID: https://orcid.org/0000-0002-5520-6239)
- Eric Stefan
- Adelajda Hadzipasic (ORCID: https://orcid.org/0000-0002-4452-8419)
- Rayan Fakih (ORCID: https://orcid.org/0000-0002-4328-618X)
- Thomas Goiran (ORCID: https://orcid.org/0000-0001-5838-8798)
- Véronique Sauvé (ORCID: https://orcid.org/0000-0002-5981-4573)
- Shimin Chen (ORCID: https://orcid.org/0000-0002-9025-093X)
- Paramasivam Murugan
- Jing Fang
Institutions
- Montreal Neurological Institute and Hospital (CA)
- Biogen (United States) (US)
- Eastern Virginia Medical School (US)
- McGill University Health Centre (CA)
- Structural Genomics Consortium (CA)
- Bristol-Myers Squibb (United States) (US)
- AureoGen Biosciences (United States) (US)
- Novartis (United States) (US)
- InterScience (United States) (US)
- Ontario Brain Institute (CA)
- McGill University (CA)
Publication Details
- Journal
- Nature Communications
- Published
- 2024-09-19
- DOI
- https://doi.org/10.1038/s41467-024-51889-3
- Citations
- 32
- Primary Topic
- biodegradable polymer synthesis and properties
- Type
- article
- Field-Weighted Citation Impact
- 5.55
Funders
- Michael J. Fox Foundation for Parkinson's Research
- Canadian Light Source
- Canada Research Chairs
- Canadian Institutes of Health Research