HECT-type ubiquitin ligases: Emerging principles in the era of full-length structures

Ubiquitin coordinates a complex network of cellular pathways through covalent modification of substrates. Specificity in substrate recognition and modification choice is largely conferred by ubiquitin ligases (E3s), a highly diversified enzyme family comprising 672 members in human cells. Among these, 28 belong to the homologous to E6AP C-terminus (HECT) family, whose distinctive structural features and functional specializations have remained incompletely understood. While the catalytic principles of the defining C-terminal HECT domain are well established, the manner in which this domain is embedded and regulated within full-length enzyme contexts long remained elusive. Over the past 5 years, a series of cryogenic electron microscopy studies have yielded unprecedented insight into the overall architectures, regulation modes, as well as linkage and substrate specificities of full-length HECT-type ligases. Here, we synthesize these advances to provide an up-to-date structural framework for HECT E3 mechanisms and highlight key questions for future investigation, including implications for small-molecule discovery.