Structural basis for phosphorylation and lysine acetylation crosstalk in a kinase motif associated with myocardial ischemia and cardioprotection
Journal article
Parker, Benjamin L., Shepherd, Nicholas E., Trefely, Sophie, Hoffman, Nolan John, White, Melanie Y., Engholm-Keller, Kasper, Hambly, Brett D., Larsen, Martin R., James, David E. and Cordwell, Stuart J.. (2014). Structural basis for phosphorylation and lysine acetylation crosstalk in a kinase motif associated with myocardial ischemia and cardioprotection. Journal of Biological Chemistry. 289(37), pp. 25890 - 25906. https://doi.org/10.1074/jbc.M114.556035
Authors | Parker, Benjamin L., Shepherd, Nicholas E., Trefely, Sophie, Hoffman, Nolan John, White, Melanie Y., Engholm-Keller, Kasper, Hambly, Brett D., Larsen, Martin R., James, David E. and Cordwell, Stuart J. |
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Abstract | Myocardial ischemia and cardioprotection by ischemic pre-conditioning induce signal networks aimed at survival or cell death if the ischemic period is prolonged. These pathways are mediated by protein post-translational modifications that are hypothesized to cross-talk with and regulate each other. Phosphopeptides and lysine-acetylated peptides were quantified in isolated rat hearts subjected to ischemia or ischemic pre-conditioning, with and without splitomicin inhibition of lysine deacetylation. We show lysine acetylation (acetyl-Lys)-dependent activation of AMP-activated protein kinase, AKT, and PKA kinases during ischemia. Phosphorylation and acetyl-Lys sites mapped onto tertiary structures were proximal in > 50% of proteins investigated, yet they were mutually exclusive in 50 ischemic pre-conditioning- and/or ischemia-associated peptides containing the KXXS basophilic protein kinase consensus motif. Modifications in this motif were modeled in the C terminus of muscle-type creatine kinase. Acetyl-Lys increased proximal dephosphorylation by 10-fold. Structural analysis of modified muscle-type creatine kinase peptide variants by two-dimensional NMR revealed stabilization via a lysine-phosphate salt bridge, which was disrupted by acetyl-Lys resulting in backbone flexibility and increased phosphatase accessibility. |
Year | 2014 |
Journal | Journal of Biological Chemistry |
Journal citation | 289 (37), pp. 25890 - 25906 |
Publisher | American Society for Biochemistry and Molecular Biology, Inc. |
ISSN | 0021-9258 |
Digital Object Identifier (DOI) | https://doi.org/10.1074/jbc.M114.556035 |
Scopus EID | 2-s2.0-84907181753 |
Open access | Open access |
Page range | 25890 - 25906 |
Research Group | Mary MacKillop Institute for Health Research |
Publisher's version | |
Place of publication | United States |
https://acuresearchbank.acu.edu.au/item/8907v/structural-basis-for-phosphorylation-and-lysine-acetylation-crosstalk-in-a-kinase-motif-associated-with-myocardial-ischemia-and-cardioprotection
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