权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

L-type Ca2+ Channel Regulation by Calmodulin and CaBP1

钙调蛋白和 CaBP1 对 L 型 Ca2 通道的调节

基本信息

批准号：
10405628
负责人：
JAMES B AMES
金额：
$ 31.4万
依托单位：
UNIVERSITY OF CALIFORNIA AT DAVIS
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-06-01 至 2024-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10405628
关键词：
Alzheimer&apos s Disease Binding Binding Sites Biological Assay Brain C-terminal CTF1 gene Calcium Calcium Binding Calcium Channel Calcium Signaling Calcium ion Calcium-Binding Proteins Calmodulin Cells Complex Computer Analysis Cryoelectron Microscopy Crystallization Dissociation EF Hand Motifs Electrophysiology (science)Epilepsy Feedback Fluorescence Gene Expression Goals Heart Heterogeneity Ion Channel Learning Link Lobe Mediating Memory Migraine Modeling Molecular Conformation Molecular Structure Mutation Mutation Analysis Neurons Nuclear Magnetic Resonance Physiological Postsynaptic Membrane Proteins Regulation Research Retina Role Sampling Signal Transduction Site-Directed Mutagenesis Structure Techniques Testing Timothy syndrome Workplace X-Ray Crystallography chronic pain in vivo insight microcalorimetry mutant nervous system disorder neuronal excitability neurotransmission postsynaptic neurons prevent response sensor voltage

项目摘要

The overall objectives are to apply nuclear magnetic resonance (NMR) techniques in concert with experimental functional approaches to elucidate the molecular structure and regulatory mechanisms of neuronal L-type voltage-gated Ca2+ channel (CaV1.2) and its atomic-level structural and functional association with calcium binding protein-1 (CaBP1), -actinin1 (ACTN1) and calmodulin (CaM). During the next five years, we will use NMR, fluorescence, microcalorimetry, cryoEM, x-ray crystallography, and computational analysis to delineate the structure and dynamics of CaM and CaBP1 each bound to CaV1.2. Site-directed mutagenesis and electrophysiology functional analysis will be integrated with atomic– level structural information to understand how CaM, ACTN1 and CaBP1 each reciprocally control the Ca2+- dependent channel activity of CaV1.2 in neuronal functions. By pursuing these studies, we hope to gain an atomic-level understanding of how CaM, ACTN1 and CaBP1 each regulate CaV1.2 involved in controlling neuronal excitability and gene expression. In particular, we want to understand how protein target binding sites work in concert with calcium-binding sites to confer Ca2+-dependent channel activity of CaV1.2 at the postsynaptic membrane. This structural information will probe how L-type channel regulation may be connected to neurological disorders, including epilepsy, Alzheimer’s disease, and Timothy Syndrome. The Specific Aims are three-fold: (1) Determine the structural basis of CaV1.2 channel activation promoted by CaM and ACTN1; (2) Elucidate the structure and functional role of a CaM intermediate with 2 Ca2+ bound and determine its role in regulating Ca2+-dependent inactivation (CDI); (3) Determine the structural basis of how CaBP1 suppresses Ca2+-dependent inactivation (CDI) of CaV1.2.

总体目标是应用核磁共振（NMR）技术