The Cardiac Ryanodine Receptor Phosphorylation Hotspot Embraces PKA in a Phosphorylation-Dependent Manner.

Ryanodine receptors (RyRs) are intracellular Ca²⁺ release channels controlling essential cellular functions. RyRs are targeted by cyclic AMP (cAMP)-dependent protein kinase A a controversial regulation implicated in disorders ranging from heart failure to Alzheimer's. Using crystal structures, we show that the phosphorylation hotspot domain of RyR2 embraces the catalytic subunit, with an extensive interface not seen in duanyu1529 complexes with peptides. We trapped an intermediary open-form duanyu1529 bound to the RyR2 domain and an ATP analog, showing that duanyu1529 can engage substrates in an open form. Phosphomimetics or prior phosphorylation at nearby sites in RyR2 either enhance or reduce the activity of Finally, we show that a phosphomimetic at S2813, a well-known target site for calmodulin-dependent kinase II, induces the formation of an alpha helix in the phosphorylation domain, resulting in increased interactions and duanyu1529 activity. This shows that the different phosphorylation sites in RyR2 are not independent.

KEYWORDS: {{ getKeywords(articleDetailText.words) }}