ArticleProceedings of the National Academy of Sciences of the United States of America2016
Cryptic sequence features within the disordered protein p27Kip1 regulate cell cycle signaling.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 79 papers.
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Who cites it
79 citing papers in PubMed.
- Article
- Methicillin treatment reveals that FtsZ phosphorylation influences the cell division ofPNAS nexus · 2026Article
- Sequence and chemical specificity define the functional landscape of intrinsically disordered regions.Nature cell biology · 2026Article
- Molecular grammars of predicted intrinsically disordered regions that span the human proteome.Cell · 2026Article
- A phase transition modulates the protective function of a tardigrade disordered protein during desiccation.Protein science : a publication of the Protein Society · 2025Article
- SAE1 promotes tumor cell malignancyActa pharmaceutica Sinica. B · 2025Article
- Context-dependent effect of polyethylene glycol on the structure and dynamics of hirudin.Biophysical journal · 2025Article
- Phosphorylation of disordered proteins tunes local and global intramolecular interactions.Biophysical journal · 2024Article
- Design of intrinsically disordered protein variants with diverse structural properties.Science advances · 2024Article
- Phosphorylation of disordered proteins tunes local and global intramolecular interactions.bioRxiv : the preprint server for biology · 2024Article
- HYPK: A marginally disordered protein sensitive to charge decoration.Proceedings of the National Academy of Sciences of the United States of America · 2024Article
- Disordered clock protein interactions and charge blocks turn an hourglass into a persistent circadian oscillator.Nature communications · 2024Article
- The molecular basis for cellular function of intrinsically disordered protein regions.Nature reviews. Molecular cell biology · 2024Review
- Article
- Intrinsically disordered regions are poised to act as sensors of cellular chemistry.Trends in biochemical sciences · 2023Review
- Challenges in Brugada Syndrome Stratification: InvestigatingInternational journal of molecular sciences · 2023Article
- Systematic identification of conditionally folded intrinsically disordered regions by AlphaFold2.Proceedings of the National Academy of Sciences of the United States of America · 2023Article
- Design of intrinsically disordered protein variants with diverse structural properties.bioRxiv : the preprint server for biology · 2023Article
- Insights into the conservation and diversification of the molecular functions of YTHDF proteins.PLoS genetics · 2023Article
- Pervasive, conserved secondary structure in highly charged protein regions.PLoS computational biology · 2023Article
19 more citing papers are in PubMed but not listed here.
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5 authors.
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Abstract
Peptide motifs embedded within intrinsically disordered regions (IDRs) of proteins are often the sites of posttranslational modifications that control cell-signaling pathways. How do IDR sequences modulate the functionalities of motifs? We answer this question using the polyampholytic C-terminal IDR of the cell cycle inhibitory protein p27(Kip1) (p27). Phosphorylation of Thr-187 (T187) within the p27 IDR controls entry into S phase of the cell division cycle. Additionally, the conformational properties of polyampholytic sequences are predicted to be influenced by the linear patterning of oppositely charged residues. Therefore, we designed sequence variants of the p27 IDR to alter charge patterning outside the primary substrate motif containing T187. Computer simulations and biophysical measurements confirm predictions regarding the impact of charge patterning on the global dimensions of IDRs. Through functional studies, we uncover cryptic sequence features within the p27 IDR that influence the efficiency of T187 phosphorylation. Specifically, we find a positive correlation between T187 phosphorylation efficiency and the weighted net charge per residue of an auxiliary motif. We also find that accumulation of positive charges within the auxiliary motif can diminish the efficiency of T187 phosphorylation because this increases the likelihood of long-range intra-IDR interactions that involve both the primary and auxiliary motifs and inhibit their contributions to function. Importantly, our findings suggest that the cryptic sequence features of the WT p27 IDR negatively regulate T187 phosphorylation signaling. Our approaches provide a generalizable strategy for uncovering the influence of sequence contexts on the functionalities of primary motifs in other IDRs.
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