Regulation of the potassium channel IK1 by calcium and histidine phosphorylation

 描述（由申请人提供）：IK 1，也称为KCa3.1或SK 4，是人体小至中电导钾通道家族（SK 1 -3，IK 1）的成员。IK 1在T细胞活化中起着至关重要的作用，通过流出钾来维持负膜电位，从而允许额外的钙流入。IK 1是自身免疫性疾病和器官移植排斥的潜在治疗靶点（用于抑制）。IK 1和SK 1 -3是四聚体，通过钙与钙调蛋白（CaM）结合而被门控/激活，钙调蛋白（CaM）与通道的细胞质部分（CaM结合结构域，CBD）内的区域结合。IK 1激活的一个新特征是CBD内特定组氨酸残基（His 358）被NDPK-B（核苷二磷酸激酶-B）磷酸化的额外要求。虽然组氨酸磷酸化在原核生物的双组分信号系统中得到了很好的表征，但真核生物中组氨酸磷酸化的程度和功能才刚刚开始被理解。最近，我们假设IK 1的组氨酸磷酸化对于解除金属离子对通道的抑制是必要的。在这个应用程序中，生化，结构和功能的研究，提出了阐明IK 1是由钙和组氨酸磷酸化调节的分子机制。

 DESCRIPTION (provided by applicant): IK1, also known as KCa3.1 or SK4, is a member of a family of small- to intermediate-conductance potassium channels in humans (SK1-3, IK1). IK1 plays a crucial role in T-cell activation by effluxing potassium to maintain a negative membrane potential that allows for additional calcium influx. IK1 is a potential therapeutic target (for inhibition) for autoimmune diseases and for organ transplant rejection. IK1 and SK1-3 are tetrameric and are gated/activated through calcium binding to calmodulin (CaM), which binds to a region within the cytoplasmic portion of the channels (CaM binding domain, CBD). A novel feature of IK1 activation is the additional requirement of phosphorylation of a specific histidine residue (His358) within the CBD by NDPK-B (nucleoside diphosphate kinase-B). Although histidine phosphorylation is well characterized in two-component signaling systems in prokaryotes, the extent and function of histidine phosphorylation in eukaryotes are just beginning to be understood. Recently, we hypothesized that histidine phosphorylation of IK1 is necessary to relieve metal- ion inhibition of the channel. In this application, biochemical, structural, and functional studies are proposed to elucidate the molecular mechanisms by which IK1 is regulated by calcium and histidine phosphorylation.