The cardiac Ryanodine receptor phosphorylation hot spot embraces PKA

Filip Van Petegem group (University of British Columbia)


When heart muscles contract, calcium ions are released from the intracellular stores in the sarcoplasmic reticulum through the specialized, 2.2-MDa ion channel known as the Ryanodine receptor (RyR). This channel of key importance in muscle contraction is the site of many mutations associated with arrhythmia, muscle weakness, and a dangerous reaction to certain anesthetics. In the heart, the RyR is under control of stress signals. For example, activation of beta-adrenergic receptors by adrenalin leads to activation of kinases (PKA, CaMKII) that can phosphorylate the RyR and facilitate channel opening and Ca2+ release. In normal conditions, this supplies the increased demand for Ca2+ during exercise or stress, but excessive phosphorylation of RyRs contributes to heart rhythm disorders, muscle fatigue, etc. The Van Petegem lab determined high-resolution crystal structures of PKA bound to its interaction domain in the RyR, which revealed the major surprise of a larger than expected interface where a long loop of the RyR forms a 'lasso' around a PKA subdomain. The interface is the site of many mutations that cause CPVT, a severe cardiac arrhythmia. In addition, the team discovered that RyR phosphorylation by CaMKII increases PKA efficiency. High-resolution structures show that the phosphorylation results in formation of a new alpha-helix, which in turn increases the affinity of PKA for the RyR.

Figure: Structure of the PKA catalytic subunit (blue surface) bound to the phosphorylation domain of RyR2, the cardiac RyR (red). A co-crystallized ATP analog is shown in spheres.


Citation: Haji-Ghassemi, O, Yuchi, Z, Van Petegem, F., The cardiac Ryanodine receptor phosphorylation hot spot embraces PKA in a phosphorylation-dependent manner, Molec. Cell 75, 1-14 (2019). DOI: 10.1016/j.molcel.2019.04.019.



GM/CA @ APS Sponsors: National Institute of General Medical Sciences (NIGMS) and National Cancer Institute (NCI) of the National Institutes of Health (NIH).

  GM/CA @ APS is an Office of Science User Facility operated for the U.S. Department of Energy by Argonne National Laboratory

  UChicago Argonne LLC | Privacy & Security Notice | Contact Us | A-Z Index | Search