Project A3 (completed)
Regulation of the SCF(b-TrCP) ubiquitin ligase via ubiquitylation of its substrate adaptor
In this project we will study the mechanisms that regulate the function of multisubunit Cullin-RING ubiquitin ligases (CRLs) - enzymes that control a range of cellular processes, including cell cycle progression, differentiation and DNA damage response. Ubiquitin transfer by CRLs is mediated by the recruitment of an E2 enzyme to the RING domain subunit Rbx1. Intriguingly, we find that CRL function is regulated by additional E2 interactions with substrate-binding subunits - the F-box proteins. We will characterize these mechanisms using X-ray crystallography and biochemical analysis and will use cell culture and mouse models to study their relevance in cell biology and tumor development.