Randall Centre for Cell and Molecular Biophysics, King's College London, SE1 1UL London, UK.
Randall Centre for Cell and Molecular Biophysics, King's College London, SE1 1UL London, UK.
Cell Rep. 2021 Jul 27;36(4):109448. doi: 10.1016/j.celrep.2021.109448.
Phospholamban (PLN) is an important regulator of cardiac calcium handling due to its ability to inhibit the calcium ATPase SERCA. β-Adrenergic stimulation reverses SERCA inhibition via PLN phosphorylation and facilitates fast calcium reuptake. PLN also forms pentamers whose physiological significance has remained elusive. Using mathematical modeling combined with biochemical and cell biological experiments, we show that pentamers regulate both the dynamics and steady-state levels of monomer phosphorylation. Substrate competition by pentamers and a feed-forward loop involving inhibitor-1 can delay monomer phosphorylation by protein kinase A (PKA), whereas cooperative pentamer dephosphorylation enables bistable PLN steady-state phosphorylation. Simulations show that phosphorylation delay and bistability act as complementary filters that reduce the effect of random fluctuations in PKA activity, thereby ensuring consistent monomer phosphorylation and SERCA activity despite noisy upstream signals. Preliminary analyses suggest that the PLN mutation R14del could impair noise filtering, offering a new perspective on how this mutation causes cardiac arrhythmias.
磷蛋白（PLN）是一种重要的心脏钙离子处理调节剂，因为它能够抑制钙 ATP 酶 SERCA。β-肾上腺素能刺激通过 PLN 磷酸化逆转 SERCA 抑制作用，促进快速钙摄取。PLN 还形成五聚体，其生理意义仍然难以捉摸。使用数学建模结合生化和细胞生物学实验，我们表明五聚体调节单体磷酸化的动力学和稳态水平。五聚体的底物竞争和涉及抑制剂-1 的正反馈环可以延迟蛋白激酶 A（PKA）对单体的磷酸化，而协同的五聚体去磷酸化使 PLN 稳定状态的磷酸化呈双稳态。模拟表明，磷酸化延迟和双稳态作为互补滤波器，可降低 PKA 活性的随机波动的影响，从而确保单体磷酸化和 SERCA 活性的一致性，尽管上游信号存在噪声。初步分析表明，PLN 突变 R14del 可能会损害噪声滤波，为该突变如何引起心律失常提供了一个新的视角。
