Ubiquitin-binding domains — from structures to functions

Abstract

Ubiquitin is an intracellular signalling molecule that is conjugated to various proteins. Ubiquitin conjugation to itself yields Lys- or Met-conjugated chains, thus expanding its repertoire of signalling networks. Ubiquitin-binding domains (UBDs) are modular elements that bind non-covalently to the protein modifier ubiquitin. Specific ubiquitin–UBD interactions are crucial for the regulation of multiple cellular functions, including protein stability, receptor trafficking, DNA damage responses and inflammatory pathways. UBD preferences for distinct ubiquitin chains of specific length and linkage are mediated through multimeric interactions, sequence context of the UBD and conformational changes following binding. Structures of ubiquitin–UBD complexes have revealed mechanisms of selectivity and specificity in their functional interactions in vivo. Defects in ubiquitin–UBD interactions are relevant for development of disease, such as inflammation and cancer. The new structure-based insights provide strategies for the design of new approaches that can therapeutically target ubiquitin–UBD interaction surfaces.