Sun Ji, MacKinnon Roderick
Laboratory of Molecular Neurobiology and Biophysics and Howard Hughes Medical Institute, The Rockefeller University, 1230 York Avenue, New York, NY 10065, USA.
Laboratory of Molecular Neurobiology and Biophysics and Howard Hughes Medical Institute, The Rockefeller University, 1230 York Avenue, New York, NY 10065, USA.
Cell. 2017 Jun 1;169(6):1042-1050.e9. doi: 10.1016/j.cell.2017.05.019.
KCNQ1 is the pore-forming subunit of cardiac slow-delayed rectifier potassium (I) channels. Mutations in the kcnq1 gene are the leading cause of congenital long QT syndrome (LQTS). Here, we present the cryoelectron microscopy (cryo-EM) structure of a KCNQ1/calmodulin (CaM) complex. The conformation corresponds to an "uncoupled," PIP-free state of KCNQ1, with activated voltage sensors and a closed pore. Unique structural features within the S4-S5 linker permit uncoupling of the voltage sensor from the pore in the absence of PIP. CaM contacts the KCNQ1 voltage sensor through a specific interface involving a residue on CaM that is mutated in a form of inherited LQTS. Using an electrophysiological assay, we find that this mutation on CaM shifts the KCNQ1 voltage-activation curve. This study describes one physiological form of KCNQ1, depolarized voltage sensors with a closed pore in the absence of PIP, and reveals a regulatory interaction between CaM and KCNQ1 that may explain CaM-mediated LQTS.
KCNQ1是心脏缓慢延迟整流钾（I）通道的孔形成亚基。kcnq1基因突变是先天性长QT综合征（LQTS）的主要原因。在此，我们展示了KCNQ1/钙调蛋白（CaM）复合物的冷冻电子显微镜（cryo-EM）结构。该构象对应于KCNQ1的“未偶联”、无磷脂酰肌醇（PIP）状态，具有激活的电压感受器和关闭的孔。S4-S5连接区内独特的结构特征允许在没有PIP的情况下电压感受器与孔解偶联。CaM通过一个特定界面与KCNQ1电压感受器接触，该界面涉及CaM上一个在遗传性LQTS的一种形式中发生突变的残基。使用电生理测定法，我们发现CaM上的这种突变会使KCNQ1电压激活曲线发生偏移。本研究描述了KCNQ1的一种生理形式，即在没有PIP的情况下具有关闭孔的去极化电压感受器，并揭示了CaM与KCNQ1之间的调节相互作用，这可能解释了CaM介导的LQTS。
