期刊
NATURE STRUCTURAL & MOLECULAR BIOLOGY
卷 29, 期 8, 页码 774-+出版社
NATURE PORTFOLIO
DOI: 10.1038/s41594-022-00807-6
关键词
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资金
- SBGrid
- NIH [DP2GM137415, F31HL157976]
- Packard Fellowship
- Vallee Foundation
- American Heart Association [287375208]
This study reveals that ubiquitin binding and a cofactor, NAP1L1, regulate the selection of protein quality-control clients by the hybrid E2/E3 enzyme UBE2O. Attaching a single ubiquitin onto a client enhances UBE2O binding and multi-mono-ubiquitylation. UBE2O also repurposes the histone chaperone NAP1L1 as an adapter to recruit a subset of clients. Cryo-EM structures of human UBE2O in complex with NAP1L1 reveal a malleable client recruitment interface that is autoinhibited by the intrinsically reactive UBC domain. Adding a ubiquitylated client identifies a distinct ubiquitin-binding SH3-like domain required for client selection. Our findings highlight how multivalency and a feed-forward mechanism drive the selection of protein quality-control clients.
Functional assays and cryo-EM structures show that ubiquitin binding and a cofactor drive protein quality-control client selection by the hybrid E2/E3 enzyme UBE2O. The E2/E3 enzyme UBE2O ubiquitylates diverse clients to mediate important processes, including targeting unassembled 'orphan' proteins for quality control and clearing ribosomes during erythropoiesis. How quality-control factors, such as UBE2O, select clients on the basis of heterogeneous features is largely unknown. Here, we show that UBE2O client selection is regulated by ubiquitin binding and a cofactor, NAP1L1. Attaching a single ubiquitin onto a client enhances UBE2O binding and multi-mono-ubiquitylation. UBE2O also repurposes the histone chaperone NAP1L1 as an adapter to recruit a subset of clients. Cryo-EM structures of human UBE2O in complex with NAP1L1 reveal a malleable client recruitment interface that is autoinhibited by the intrinsically reactive UBC domain. Adding a ubiquitylated client identifies a distinct ubiquitin-binding SH3-like domain required for client selection. Our findings reveal how multivalency and a feed-forward mechanism drive the selection of protein quality-control clients.
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