Journal
NATURE CHEMICAL BIOLOGY
Volume 17, Issue 10, Pages 1084-1092Publisher
NATURE PORTFOLIO
DOI: 10.1038/s41589-021-00831-5
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Funding
- European Research Council under the European Union's Horizon 2020 research and innovation program [AdG 694978]
- Marie Skodowska-Curie grant [847548]
- FFG Headquarter grant [852936]
- Austrian Science Fund [SFB F 79]
- Boehringer Ingelheim
- Marie Curie Actions (MSCA) [847548] Funding Source: Marie Curie Actions (MSCA)
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HUWE1 is a universal quality-control E3 ligase, whose crystal structure reveals its specificity for marking diverse, unrelated substrates. It adopts a unique snake-like structure, with a highly dynamic ring structure facilitating interaction with various protein targets.
HUWE1 is a universal quality-control E3 ligase that marks diverse client proteins for proteasomal degradation. Although the giant HECT enzyme is an essential component of the ubiquitin-proteasome system closely linked with severe human diseases, its molecular mechanism is little understood. Here, we present the crystal structure of Nematocida HUWE1, revealing how a single E3 enzyme has specificity for a multitude of unrelated substrates. The protein adopts a remarkable snake-like structure, where the C-terminal HECT domain heads an extended alpha-solenoid body that coils in on itself and houses various protein-protein interaction modules. Our integrative structural analysis shows that this ring structure is highly dynamic, enabling the flexible HECT domain to reach protein targets presented by the various acceptor sites. Together, our data demonstrate how HUWE1 is regulated by its unique structure, adapting a promiscuous E3 ligase to selectively target unassembled orphan proteins.
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