Rohl C A, Boeckman F A, Baker C, Scheuer T, Catterall W A, Klevit R E
Department of Biochemistry, University of Washington, Seattle 98195, USA.
Biochemistry. 1999 Jan 19;38(3):855-61. doi: 10.1021/bi9823380.
The sodium channel initiates action potentials by opening in response to membrane depolarization. Fast channel inactivation, which is required for proper physiological function, is mediated by a cytoplasmic loop proposed to occlude the ion pore via a hinged lid mechanism with the triad IFM serving as a hydrophobic "latch". The NMR solution structure of the isolated inactivation gate reveals a stably folded core comprised of an alpha-helix capped by an N-terminal turn, supporting a model in which the tightly folded core containing the latch motif pivots on a more flexible hinge region to occlude the pore during inactivation. The structure, in combination with substituted cysteine mutagenesis experiments, indicates that the IFM triad and adjacent Thr are essential components of the latch and suggests differing roles for the residues of the IFMT motif in fast inactivation.
钠通道通过响应膜去极化而开放来启动动作电位。快速通道失活是正常生理功能所必需的，它由一个胞质环介导，该胞质环被认为通过一种铰链盖机制封闭离子孔，其中三联体IFM作为一个疏水“锁扣”。分离的失活门的核磁共振溶液结构揭示了一个稳定折叠的核心，该核心由一个由N端转角封端的α螺旋组成，支持了一个模型，即在失活过程中，包含锁扣基序的紧密折叠核心在一个更灵活的铰链区域上旋转以封闭孔。该结构与取代半胱氨酸诱变实验相结合，表明IFM三联体和相邻的苏氨酸是锁扣的重要组成部分，并暗示了IFMT基序的残基在快速失活中的不同作用。
