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

摘要： 钙调素（CaM）是一种多功能的钙离子结合蛋白，在多种细胞内钙离子的代谢中起着重要作用。 胞内信号传导它协调了许多关键的细胞过程。CaM由3种不同的 人类中的基因，即CALM 1、CALM 2和CALM 3，其每一个编码相同的CaM分子 在蛋白质水平上。CaM，一种17 kDa的蛋白质，由通过柔性螺旋连接的N-和C-末端叶组成。 每个叶包含两个EF手，典型的Ca 2+结合基序，N叶具有略低的Ca 2 + 结合亲和力Ca 2+与EF手的结合导致靶标的结构和功能变化 分子。最近的研究提供了人类可遗传的CaM突变与几种 心律失常和心源性猝死的类型，包括儿茶酚胺能多形心室 心动过速（CPVT）、长QT综合征（LQTS）和家族性特发性心室颤动（IVF）。 拟议的研究将使用计算分析的组合，包括罗塞塔计算 建模和分子动力学（MD）模拟以及实验方法来破译 与LQTS机制相关的突变CaM对心脏离子通道（包括Na+）的分子效应， Ca 2+和Ca 2+依赖性K+通道。我们设想了一个迭代过程，其中分子建模将 为实验设计提供信息，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.