HECT-Type Ubiquitin Ligases: Emerging principles in the Era of Full-Length Structures

The ubiquitin system coordinates an increasingly intricate network of cellular pathways. Specificity in substrate recognition and ubiquitin modification is largely conferred by ubiquitin ligases, a highly diversified enzyme family comprising 672 members in human cells. Among these, 28 belong to the HECT (Homologous to E6AP C-terminus) 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 within, and regulated by, full-length enzymes long remained elusive. Over the past five years, a series of cryo-electron microscopy studies of full-length HECT-type ligases have yielded unprecedented insights into their overall architectures, regulatory mechanisms, and linkage and substrate specificities. Here, we synthesize these advances to provide an up-to-date structural framework for HECT-type ligase function and highlight key questions for future investigation, including implications for small-molecule discovery.