EMD-16370

Single-particle
8.2 Å
EMD-16370 Deposition: 18/12/2022
Map released: 08/03/2023
Last modified: 13/12/2023
Overview 3D View Sample Experiment Validation Volume Browser Additional data Links
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EMD-16370

Structure of CUL2-KLHDC2 E3 ligase autoinhibited by C-degron mimicry

EMD-16370

Single-particle
8.2 Å
EMD-16370 Deposition: 18/12/2022
Map released: 08/03/2023
Last modified: 13/12/2023
Overview 3D View Sample Experiment Validation Volume Browser Additional data Links
Sample Organism: Homo sapiens
Sample: Structure of CUL2-KLHDC2 E3 ligase autoinhibited by C-degron mimicry

Deposition Authors: Scott DC , King M , Baek K , Schulman BA
E3 ligase autoinhibition by C-degron mimicry maintains C-degron substrate fidelity.
PUBMED: 36805027
DOI: doi:10.1016/j.molcel.2023.01.019
ISSN: 1097-2765
ASTM: MOCEFL
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 CRL2KLHDC2, 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 CRL2KLHDC2. Without substrate, neddylated CRL2KLHDC2 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.