Functional and molecular mechanisms of human calmodulinopathy in cardiac arrhythmias and sudden cardiac death

摘要： 钙调蛋白(CaM)是一种多功能的钙离子结合蛋白，在多种生理功能中发挥重要作用。 细胞内信号。它协调了许多关键的细胞过程。凸轮由3个不同的编码 人类的基因，即CALM1、CALM2和CALM3，每个基因编码一个相同的CaM分子 在蛋白质水平上。CaM是一种17 kDa的蛋白质，由N-端和C-端的小叶通过一个柔性螺旋相连。 每个叶包含两个EF手，典型的钙结合模体，N叶的钙离子略低 结合亲和力。Ca~(2+)与EF结合导致靶的结构和功能改变 分子。最近的研究提供了人类可遗传CaM突变与几个 包括儿茶酚胺能多形性室性心律失常和心脏性猝死的类型 心动过速(CPVT)、长QT综合征(LQTS)和家族性特发性室颤(IVF)。 拟议的研究将使用计算分析的组合，包括Rosetta计算 建模和分子动力学(MD)模拟以及破译 突变的CaM对包括Na+在内的心脏离子通道的分子效应与LQTS的作用机制有关。 Ca~(2+)和钙依赖的K~+通道。我们设想了一个重复的过程，在这个过程中，分子建模将 告知实验设计，反之亦然。

Abstract: Calmodulin (CaM) is a multifunctional Ca2+ binding protein that plays important roles in a wide range of intracellular signaling. It orchestrates a number of critical cellular processes. CaM is encoded by 3 distinct genes in human, namely CALM1, CALM2, and CALM3, each of which encodes for an identical CaM molecule at the protein level. CaM, a 17 kDa protein comprised of N- and C-terminal lobes linked by a flexible helix. Each lobe contains two EF hands, canonical Ca2+ binding motifs, with the N-lobe having slightly lower Ca2+ binding affinity. Ca2+ binding to the EF hands results in structural and functional changes of the target molecules. Recent studies have provided genetics links between human heritable CaM mutations to several types of cardiac arrhythmias and sudden cardiac death including catecholaminergic polymorphic ventricular tachycardia (CPVT), long QT syndrome (LQTS), and familial idiopathic ventricular fibrillation (IVF). The proposed study will use a combination of computational analyses including Rosetta computational modeling and molecular dynamics (MD) simulations as well as experimental approaches to decipher the molecular effects of mutant CaMs, linked to mechanisms of LQTS, on cardiac ion channels including Na+, Ca2+, and Ca2+-dependent K+ channels. We envision a reiterative process whereby the molecular modeling will inform the experimental designs and vice versa.