ArticleProceedings of the National Academy of Sciences of the United States of America2022
The optimal docking strength for reversibly tethered kinases.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 13 papers.
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13 citing papers in PubMed, 30 citations in OpenAlex.
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- The molecular basis for cellular function of intrinsically disordered protein regions.Nature reviews. Molecular cell biology · 2024Review
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- Linear motif specificity in signaling through p38α and ERK2 mitogen-activated protein kinases.Proceedings of the National Academy of Sciences of the United States of America · 2023Article
- Sequence-ensemble-function relationships for disordered proteins in live cells.bioRxiv : the preprint server for biology · 2023Article
- Sequence-ensemble-function relationships for disordered proteins in live cells.Research square · 2023Article
- Phosphorylation-Assisted Luciferase Complementation Assay Designed to Monitor Kinase Activity and Kinase-Domain-Mediated Protein-Protein Binding.International journal of molecular sciences · 2023Article
- Thumb-domain dynamics modulate the functional repertoire of DNA-Polymerase IV (DinB).Nucleic acids research · 2023Article
- Enhancing the Catalytic Activity of Thermo-Asparaginase fromInternational journal of molecular sciences · 2023Article
- PERIOD phosphorylation leads to feedback inhibition of CK1 activity to control circadian period.Molecular cell · 2023Article
- The biophysics of disordered proteins from the point of view of single-molecule fluorescence spectroscopy.Essays in biochemistry · 2022Article
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Authors and funding
4 authors at 1 institution in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Many kinases use reversible docking interactions to augment the specificity of their catalytic domains. Such docking interactions are often structurally independent of the catalytic domain, which allow for a flexible combination of modules in evolution and in bioengineering. The affinity of docking interactions spans several orders of magnitude. This led us to ask how the affinity of the docking interaction affects enzymatic activity and how to pick the optimal interaction module to complement a given substrate. Here, we develop equations that predict the optimal binding strength of a kinase docking interaction and validate it using numerical simulations and steady-state phosphorylation kinetics for tethered protein kinase A. We show that a kinase-substrate pair has an optimum docking strength that depends on their enzymatic constants, the tether architecture, the substrate concentration, and the kinetics of the docking interactions. We show that a reversible tether enhances phosphorylation rates most when 1) the docking strength is intermediate, 2) the substrate is nonoptimal, 3) the substrate concentration is low, 4) the docking interaction has rapid exchange kinetics, and 5) the tether optimizes the effective concentration of the intramolecular reaction. This work serves as a framework for interpreting mutations in kinase docking interactions and as a design guide for engineering enzyme scaffolds.
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