Summary
HECT ubiquitin ligases play essential roles in metazoan development and physiology. The HECT ligase HUWE1 is central to the cellular stress response by mediating degradation of key death or survival factors including Mcl1, p53, DDIT4, and Myc. As a step toward understanding regulation of HUWE1 engagement with its diverse substrates, we present here the cryo-EM structure of HUWE1, offering a first complete molecular picture of a HECT ubiquitin ligase. The ~4400 amino acid residue polypeptide forms an alpha solenoid-shaped assembly with a central pore decorated with protein interaction modules. This modularity enables HUWE1 to target a wide range of substrates for destruction. The locations of human mutations associated with severe neurodevelopmental disorders link functions of this essential enzyme with its three-dimensional organization.
Competing Interest Statement
E.S.F. is a founder, scientific advisory board, and equity holder in Civetta Therapeutics, Jengu Therapeutics, and Neomorph. E.S.F. is an equity holder in C4 Therapeutics and a consultant to Novartis, AbbVie, EcoR1 capital, Deerfield, and Astellas. The Fischer lab receives or has received research funding from Novartis, Deerfield and Astellas.
Footnotes
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