12: MUTYH's allosteric [4Fe-4S] network

Trasviña-Arenas CH et al., Nature Communications - This episode explores a 2025 study that reports the first human MUTYH structure bound to a transition state analog and functional profiling of cancer-associated variants near its [4Fe-4S] cluster. The authors map an evolutionarily conserved hydrogen-bond network linking the metal cluster to the catalytic Asp236 and show how specific variants disrupt catalysis. Two variants (R241Q, N238S) retain metal binding and DNA affinity yet lose glycosylase activity, revealing an allosteric regulatory role for the cofactor. Molecular dynamics and a bacterial homolog structure support a model in which the cluster positions and modulates the catalytic residue to enable adenine excision. Key terms: MUTYH, 4Fe-4S cluster, base excision repair, allosteric network, cancer-associated variants.

Study Highlights:
Researchers solved a 1.9 Å human MUTYH–transition state analog crystal structure that uncovers a hydrogen-bond bridge from the [4Fe-4S] cluster to the active site. Functional profiling of 12 cancer-associated variants near the cluster shows most lose cofactors and activity, while R241Q and N238S uniquely retain metals and DNA binding but are inactive. A corresponding bacterial R149Q structure and molecular dynamics reveal alternate cluster conformations and altered dynamics that disrupt communication to catalytic Asp236. Together the data support an allosteric network that positions and affects the protonation state of Asp236 to enable base excision.

Conclusion:
The [4Fe-4S] cluster in MUTYH is an active allosteric element connected to the catalytic pocket via a conserved Cys290–Arg241–Asn238–Asp236 hydrogen-bond network; disruption of this bridge by cancer-associated variants can disable DNA repair even when metal binding and DNA affinity are retained, highlighting a mechanism for MUTYH-associated mutagenesis and a potential regulatory or therapeutic target.

QC:
This episode was checked against the original article PDF and publication metadata.
Scope: article metadata and core scientific claims from the narration, excluding analogies, intro/outro, and music.
Factual QC score: 10/10.
Metadata QC score: 10/10.
Supported core claims: 8.
Claims flagged for review: 0.
Metadata checks passed: 6.
Metadata issues found: 0.
QC result: Pass.

Music:
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Article title:
Structure of human MUTYH and functional profiling of cancer-associated variants reveal an allosteric network between its [4Fe-4S] cluster cofactor and active site required for DNA repair

First author:
Trasviña-Arenas CH

Journal:
Nature Communications

DOI:
10.1038/s41467-025-58361-w

Reference:
Trasviña-Arenas CH, Dissanayake UC, Tamayo N, et al. Structure of human MUTYH and functional profiling of cancer-associated variants reveal an allosteric network between its [4Fe-4S] cluster cofactor and active site required for DNA repair. Nature Communications. 2025;16:3596. doi:10.1038/s41467-025-58361-w

License:
Creative Commons Attribution 4.0 International (CC BY 4.0)

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