EMD-16370
Structure of CUL2-KLHDC2 E3 ligase autoinhibited by C-degron mimicry
EMD-16370
Single-particle8.2 Å
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Map released: 08/03/2023
Last modified: 13/12/2023
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
Sample: Structure of CUL2-KLHDC2 E3 ligase autoinhibited by C-degron mimicry
Deposition Authors: Scott DC
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E3 ligase autoinhibition by C-degron mimicry maintains C-degron substrate fidelity.
Scott DC
,
King MT,
Baek K
,
Gee CT
,
Kalathur R,
Li J
,
Purser N
,
Nourse A
,
Chai SC,
Vaithiyalingam S,
Chen T,
Lee RE
,
Elledge SJ,
Kleiger G,
Schulman BA
(2023) Mol Cell , 83 , 770 - 786.e9
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(2023) Mol Cell , 83 , 770 - 786.e9
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.
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.