Assembly, activation and function of JAMM/MPN deubiquitylating complexes (360G-Wellcome-200523_Z_16_Z)

Ubiquitin is attached as a post-translational modification to protein substrates either as mono- or poly-ubiquitylation by ubiquitin ligases. This serves to regulate cellular signalling events and virtually all aspects of cellular life. Malfunctioning of signalling networks controlled by protein ubiquitylation can lead to diseases such as cancer, neurodegeneration and inflammation. Deubiquitylating enzymes (DUBs) remove ubiquitin from substrates and counteract the roles of ubiquitin ligases. There are approximately 100 DUBs, which belong to five families. The JAMM/MPN DUB family is unique in using Zn2+ for catalysis. Seven out of 14 family members are predicted to be catalytically active (denoted MPN+) while the others, which bear substitutions to essential catalytic residues, are predicted to be catalytically dead (denoted MPN–). MPN DUBs typically function within larger multi-subunit complexes, which imparts great potential for multi-layer regulation. BRCC36 is an MPN+ DUB that forms two multimeric complexes: a cytoplasmic BRISC-SHMT2 complex that regulates intereferon signaling, and a nuclear ARISC-RAP80 complex that is required for DNA damage response. I seek to uncover the structural and functional basis by which BRCC36 containing complexes select their specific substrates, are regulated by physiological means, and are modulated by small molecules that have the potential to serve as therapeutics.