Introduction

Abstract

Protein ubiquitylation is one of the most important posttranslational protein modifications, catalyzed by an enzyme cascade of E1/E2/E3. Neddylation, like ubiquitylation, is also catalyzed by an E1/E2/E3 enzyme cascade to covalently attach the ubiquitin-like molecule NEDD8 to a lysine residue of a substrate, not for degradation, but for modulation of substrate activity. The best known neddylation substrates are cullin family members, the scaffold component of the cullin-RING ligase (CRL), which is the largest family of E3 ligases that catalyze the ubiquitylation of ~20% of cellular proteins doomed for the degradation by proteasome system. The activity of CRLs requires cullin neddylation, which facilitates the adaptation of CRLs to an open conformation for easy substrate access. Since the substrates of CRLs are various key molecules that regulate a variety of cellular functions, CRLs and their neddylation activation, therefore, play the essential roles in many biological processes. Indeed, CRLs are abnormally regulated in many human diseases and serve as the therapeutic targets at least for cancer. This book will summarize most recent progress in this field with three sections, covering (1) structure and regulation of CRL and neddylation, (2) biological function of each CRLs, and (3) drug discovery efforts to target CRL/neddylation for cancer therapy.