Mechanism and regulation of the Lys6-selective deubiquitinase USP30

DOI: 10.1038/nsmb.3475

Authors: Malte Gersch (Medical Research Council Laboratory of Molecular Biology) , Christina Gladkova (Medical Research Council Laboratory of Molecular Biology) , Alexander F. Schubert (Medical Research Council Laboratory of Molecular Biology) , Martin A. Michel (Medical Research Council Laboratory of Molecular Biology) , Sarah Maslen (Medical Research Council Laboratory of Molecular Biology) , David Komander (Medical Research Council Laboratory of Molecular Biology)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: Nature Structural & Molecular Biology

State: Published (Approved)
Published: September 2017

Abstract: Damaged mitochondria undergo mitophagy, a specialized form of autophagy that is initiated by the protein kinase PINK1 and the ubiquitin E3 ligase Parkin. Ubiquitin-specific protease USP30 antagonizes Parkin-mediated ubiquitination events on mitochondria and is a key negative regulator of mitophagy. Parkin and USP30 both show a preference for assembly or disassembly, respectively, of Lys6-linked polyubiquitin, a chain type that has not been well studied. Here we report crystal structures of human USP30 bound to monoubiquitin and Lys6-linked diubiquitin, which explain how USP30 achieves Lys6-linkage preference through unique ubiquitin binding interfaces. We assess the interplay between USP30, PINK1 and Parkin and show that distally phosphorylated ubiquitin chains impair USP30 activity. Lys6-linkage-specific affimers identify numerous mitochondrial substrates for this modification, and we show that USP30 regulates Lys6-polyubiquitinated TOM20. Our work provides insights into the architecture, activity and regulation of USP30, which will aid drug design against this and related enzymes.

Journal Keywords: Autophagy; Mitochondrial proteins; Ubiquitins; X-ray crystallography

Diamond Keywords: Enzymes; Parkinson’s Disease

Subject Areas: Biology and Bio-materials


Instruments: I02-Macromolecular Crystallography , I04-1-Macromolecular Crystallography (fixed wavelength) , I24-Microfocus Macromolecular Crystallography

Added On: 27/09/2017 09:27

Discipline Tags:

Neurodegenerative Diseases Health & Wellbeing Neurology Structural biology Drug Discovery Life Sciences & Biotech

Technical Tags:

Diffraction Macromolecular Crystallography (MX)