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E3 ligase autoinhibition by C-degron mimicry maintains C-degron substrate fidelity.
- Source :
-
Molecular cell [Mol Cell] 2023 Mar 02; Vol. 83 (5), pp. 770-786.e9. Date of Electronic Publication: 2023 Feb 16. - Publication Year :
- 2023
-
Abstract
- E3 ligase recruitment of proteins containing terminal destabilizing motifs (degrons) is emerging as a major form of regulation. How those E3s discriminate bona fide substrates from other proteins with terminal degron-like sequences remains unclear. Here, we report that human KLHDC2, a CRL2 substrate receptor targeting C-terminal Gly-Gly degrons, is regulated through interconversion between two assemblies. In the self-inactivated homotetramer, KLHDC2's C-terminal Gly-Ser motif mimics a degron and engages the substrate-binding domain of another protomer. True substrates capture the monomeric CRL2 <superscript>KLHDC2</superscript> , driving E3 activation by neddylation and subsequent substrate ubiquitylation. Non-substrates such as NEDD8 bind KLHDC2 with high affinity, but its slow on rate prevents productive association with CRL2 <superscript>KLHDC2</superscript> . Without substrate, neddylated CRL2 <superscript>KLHDC2</superscript> assemblies are deactivated via distinct mechanisms: the monomer by deneddylation and the tetramer by auto-ubiquitylation. Thus, substrate specificity is amplified by KLHDC2 self-assembly acting like a molecular timer, where only bona fide substrates may bind before E3 ligase inactivation.<br />Competing Interests: Declaration of interests B.A.S. is a member of the scientific advisory boards of Interline Therapeutics and BioTheryX. B.A.S. and D.C.S. are co-inventors of intellectual property licensed to Cinsano.<br /> (Copyright © 2023 Elsevier Inc. All rights reserved.)
- Subjects :
- Humans
Carrier Proteins
Proteins metabolism
Ubiquitin-Protein Ligases metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 1097-4164
- Volume :
- 83
- Issue :
- 5
- Database :
- MEDLINE
- Journal :
- Molecular cell
- Publication Type :
- Academic Journal
- Accession number :
- 36805027
- Full Text :
- https://doi.org/10.1016/j.molcel.2023.01.019