环腺苷酸与 HCN 通道 C 末端结合的能量学揭示了负协同性。
Energetics of cyclic AMP binding to HCN channel C terminus reveal negative cooperativity.
机构信息
Department of Cellular and Physiological Sciences, University of British Columbia, Vancouver, British Columbia, V6T 1Z3, Canada.
Department of Biochemistry and Molecular Biology, University of British Columbia, Vancouver, British Columbia V6T 1Z3, Canada.
出版信息
J Biol Chem. 2012 Jan 2;287(1):600-606. doi: 10.1074/jbc.M111.269563. Epub 2011 Nov 14.
Abstract
Cyclic AMP binds to the HCN channel C terminus and variably stabilizes its open state. Using isothermal titration calorimetry, we show that cAMP binds to one subunit of tetrameric HCN2 and HCN4 C termini with high affinity (∼0.12 μM) and subsequently with low affinity (∼1 μM) to the remaining three subunits. Changes induced by high affinity binding already exist in both a constrained HCN2 tetramer and the unconstrained HCN1 tetramer. Natural "preactivation" of HCN1 may explain both the smaller effect of cAMP on stabilizing its open state and the opening of unliganded HCN1, which occurs as though already disinhibited.
摘要
环磷酸腺苷与 HCN 通道 C 末端结合，并可使该通道的开放状态发生不同程度的稳定。通过使用等温滴定量热法，我们发现 cAMP 以高亲和力（约 0.12 μM）结合于四聚体 HCN2 和 HCN4 C 末端的一个亚基上，随后以低亲和力（约 1 μM）结合于剩余的三个亚基上。高亲和力结合所诱导的构象变化在受到约束的 HCN2 四聚体和不受约束的 HCN1 四聚体中均已存在。HCN1 的天然“预激活”可能解释了 cAMP 对稳定其开放状态的影响较小，以及未结合配体的 HCN1 也会发生开放的原因，这就好像 HCN1 已经去抑制了一样。
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