Sauvé, Véronique, Stefan, Eric, Croteau, Nathalie, Goiran, Thomas, Fakih, Rayan, Bansal, Nupur, Hadzipasic, Adelajda, Fang, Jing, Murugan, Paramasivam, Chen, Shimin, Fon, Edward A, Hirst, Warren D, Silvian, Laura F, Trempe, Jean-François and Gehring, Kalle (2024) Activation of parkin by a molecular glue. Nature communications, 15 (1). p. 7707. ISSN 2041-1723

Abstract

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.

Item Type:	Article
Date Deposited:	10 Oct 2024 00:45
Last Modified:	10 Oct 2024 00:45
URI:	https://oak.novartis.com/id/eprint/55445