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| Title | High-throughput investigation of cyclin docking interactions reveals the complexity of motif binding determinants. |
|---|---|
| Journal, issue, pages | Nat Commun, Vol. 16, Issue 1, Page 7622, Year 2025 |
| Publish date | Aug 15, 2025 |
Authors | Mihkel Örd / Matthew J Winters / Mythili S Subbanna / Natàlia de Martín Garrido / Victoria I Cushing / Johanna Kliche / Caroline Benz / Ylva Ivarsson / Basil J Greber / Peter M Pryciak / Norman E Davey / ![]() |
| PubMed Abstract | Many regulatory protein-protein interactions depend on Short Linear Motifs (SLiMs). In the cell cycle, cyclin-CDKs recognize SLiMs to control substrate recruitment and phosphorylation timing. Here, ...Many regulatory protein-protein interactions depend on Short Linear Motifs (SLiMs). In the cell cycle, cyclin-CDKs recognize SLiMs to control substrate recruitment and phosphorylation timing. Here, we measure the relative binding strength of ~100,000 peptides to 11 human cyclins from five families (D, E, A, B, and F). Using a quantitative intracellular binding assay and large-scale tiled peptide screening, we identify multiple non-canonical binders unveiling a broader repertoire of cyclin docking motif types. Cryo-electron microscopy and saturation mutagenesis studies reveal distinct binding modes and sequence features governing motif recognition, binding strength, and cyclin preference. Docking motifs vary from highly selective to pan-cyclin, thereby fine-tuning the timing of CDK phosphorylation during cell cycle. Overall, these findings provide insights into the rules encoding specificity and affinity of SLiM-mediated interactions and offer a framework for understanding motif-driven protein networks across the proteome. |
External links | Nat Commun / PubMed:40817109 / PubMed Central |
| Methods | EM (single particle) |
| Resolution | 2.9 - 3.2 Å |
| Structure data | EMDB-52201, PDB-9hiu: EMDB-52204, PDB-9hiw: EMDB-52208, PDB-9hj1: |
| Source |
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Keywords | CELL CYCLE / Kinase / cyclin / short linear motif / cdk2 / cyclin A |
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homo sapiens (human)
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