ArticleThe Journal of biological chemistry2011
Autophosphorylation activates Dictyostelium myosin II heavy chain kinase A by providing a ligand for an allosteric binding site in the alpha-kinase domain.
Article in The Journal of biological chemistry, 2011. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 18 papers.
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Who cites it
18 citing papers in PubMed, 24 citations in OpenAlex.
- Identification of 14-3-3 Proteins as Binding Partners of TRP Channels.Journal of chemical information and modeling · 2026Article
- eEF2K Inhibitor Design: The Progression of Exemplary Structure-Based Drug Design.Molecules (Basel, Switzerland) · 2023Review
- Sampling alternative conformational states of transporters and receptors with AlphaFold2.eLife · 2022Article
- Synthesis and Assembly of Hepatitis B Virus-Like Particles in aFrontiers in bioengineering and biotechnology · 2020Article
- Eukaryotic Elongation Factor 2 Kinase (eEF2K) in Cancer.Cancers · 2017Review
- Mass Spectrometric Analysis of TRPM6 and TRPM7 Phosphorylation Reveals Regulatory Mechanisms of the Channel-Kinases.Scientific reports · 2017Article
- Structure of the Dictyostelium Myosin-II Heavy Chain Kinase A (MHCK-A) α-kinase domain apoenzyme reveals a novel autoinhibited conformation.Scientific reports · 2016Article
- Eukaryotic elongation factor 2 kinase as a drug target in cancer, and in cardiovascular and neurodegenerative diseases.Acta pharmacologica Sinica · 2016Review
- Characterization of the Catalytic and Nucleotide Binding Properties of the α-Kinase Domain of Dictyostelium Myosin-II Heavy Chain Kinase A.The Journal of biological chemistry · 2015Article
- The molecular mechanism of eukaryotic elongation factor 2 kinase activation.The Journal of biological chemistry · 2014Article
- A conserved loop in the catalytic domain of eukaryotic elongation factor 2 kinase plays a key role in its substrate specificity.Molecular and cellular biology · 2014Article
- SIMS: a hybrid method for rapid conformational analysis.PloS one · 2013Article
- Significant reduction in errors associated with nonbonded contacts in protein crystal structures: automated all-atom refinement with PrimeX.Acta crystallographica. Section D, Biological crystallography · 2012Article
- Calcium/calmodulin stimulates the autophosphorylation of elongation factor 2 kinase on Thr-348 and Ser-500 to regulate its activity and calcium dependence.Biochemistry · 2012Article
- Identification of autophosphorylation sites in eukaryotic elongation factor-2 kinase.The Biochemical journal · 2012Article
- Insights into the regulation of eukaryotic elongation factor 2 kinase and the interplay between its domains.The Biochemical journal · 2012Article
- Rosetta FlexPepDock web server--high resolution modeling of peptide-protein interactions.Nucleic acids research · 2011Article
- Rosetta FlexPepDock ab-initio: simultaneous folding, docking and refinement of peptides onto their receptors.PloS one · 2011Article
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Authors and funding
9 authors at 3 institutions in 2 countries.
Funding
Abstract
Dictyostelium discoideum myosin II heavy chain kinase A (MHCK A), a member of the atypical α-kinase family, phosphorylates sites in the myosin II tail that block filament assembly. Here we show that the catalytic activity of A-CAT, the α-kinase domain of MHCK A (residues 552-841), is severely inhibited by the removal of a disordered C-terminal tail sequence (C-tail; residues 806-841). The key residue in the C-tail was identified as Thr(825), which was found to be constitutively autophosphorylated. Dephosphorylation of Thr(825) using shrimp alkaline phosphatase decreased A-CAT activity. The activity of a truncated A-CAT lacking Thr(825) could be rescued by P(i), phosphothreonine, and a phosphorylated peptide, but not by threonine, glutamic acid, aspartic acid, or an unphosphorylated peptide. These results focused attention on a P(i)-binding pocket located in the C-terminal lobe of A-CAT. Mutational analysis demonstrated that the P(i)-pocket was essential for A-CAT activity. Based on these results, it is proposed that autophosphorylation of Thr(825) activates ACAT by providing a covalently tethered ligand for the P(i)-pocket. Ab initio modeling studies using the Rosetta FloppyTail and FlexPepDock protocols showed that it is feasible for the phosphorylated Thr(825) to dock intramolecularly into the P(i)-pocket. Allosteric activation is predicted to involve a conformational change in Arg(734), which bridges the bound P(i) to Asp(762) in a key active site loop. Sequence alignments indicate that a comparable regulatory mechanism is likely to be conserved in Dictyostelium MHCK B-D and metazoan eukaryotic elongation factor-2 kinases.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.