Distinct functional constraints driving conservation of the cofilin N-terminal regulatory tail
- PMID: 38365893
- PMCID: PMC10873347
- DOI: 10.1038/s41467-024-45878-9
Distinct functional constraints driving conservation of the cofilin N-terminal regulatory tail
Abstract
Cofilin family proteins have essential roles in remodeling the cytoskeleton through filamentous actin depolymerization and severing. The short, unstructured N-terminal region of cofilin is critical for actin binding and harbors the major site of inhibitory phosphorylation. Atypically for a disordered sequence, the N-terminal region is highly conserved, but specific aspects driving this conservation are unclear. Here, we screen a library of 16,000 human cofilin N-terminal sequence variants for their capacity to support growth in S. cerevisiae in the presence or absence of the upstream regulator LIM kinase. Results from the screen and biochemical analysis of individual variants reveal distinct sequence requirements for actin binding and regulation by LIM kinase. LIM kinase recognition only partly explains sequence constraints on phosphoregulation, which are instead driven to a large extent by the capacity for phosphorylation to inactivate cofilin. We find loose sequence requirements for actin binding and phosphoinhibition, but collectively they restrict the N-terminus to sequences found in natural cofilins. Our results illustrate how a phosphorylation site can balance potentially competing sequence requirements for function and regulation.
© 2024. The Author(s).
Conflict of interest statement
The authors declare no competing interests.
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Distinct functional constraints driving conservation of the cofilin N-terminal regulatory tail.bioRxiv [Preprint]. 2023 Jul 9:2023.06.30.547189. doi: 10.1101/2023.06.30.547189. bioRxiv. 2023. Update in: Nat Commun. 2024 Feb 16;15(1):1426. doi: 10.1038/s41467-024-45878-9. PMID: 37425676 Free PMC article. Updated. Preprint.
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