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Structural, Functional, and Mechanistic Diversity in Protein Ubiquitination

Protein ubiquitination is a regulatory process with far‐reaching impacts on all aspects of eukaryotic biology. It is involved in every known biological process and is implicated in a growing range of diseases including, but not limited to, cancers, neurodegenerative diseases, and muscle wasting. The language of ubiquitin signaling is incredibly rich. Cellular proteins may be modified with one or more single ubiquitin (Ub) moieties or with poly‐Ub chains. The most common configuration of poly‐Ub is the so‐called Lys48‐linked chain, long known to target proteins for degradation by the proteasome. But it is now clear that any of seven possible lysine linkages as well as linear linkages (N‐terminus‐to‐C‐terminus) and mixed chains are all generated in cells. This results in a remarkable array of outcomes, both at the level of a modified protein and at a cellular level. Three basic enzymatic activities (i.e., E1, E2, and E3) work in series to carry out protein ubiquitination and are ultimately responsible for the variety observed. Decades of research have provided insights regarding shared structural and mechanistic features in each class of enzyme. More recently, novel and unexpected features of individual members of the E2 and E3 families have also led to important conceptual advances in our understanding of Ub transfer and signaling. I will present the general structural and mechanistic features of protein ubiquitination and several recent examples of how highly related enzymes have evolved to perform in specialized ways. Not only do such discoveries contribute to our understanding of the source of diversity in protein ubiquitination, they also provide new avenues with which to understand the rich and varied functions of this essential regulatory system.