National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS)
DP2GM137415
米国
David and Lucile Packard Foundation
2019-69660
米国
Other private
Vallee Foundation
American Heart Association
287375208
米国
National Institutes of Health/National Heart, Lung, and Blood Institute (NIH/NHLBI)
F31HL157976
米国
引用
ジャーナル: Nat Struct Mol Biol / 年: 2022 タイトル: Mechanism of client selection by the protein quality-control factor UBE2O. 著者: Matthew C J Yip / Samantha F Sedor / Sichen Shao / 要旨: 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. ...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.