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Obscurin-kinase 1/N-cadherin: a new signaling axis in cardiac structure/function

暗蛋白激酶 1/N-钙粘蛋白：心脏结构/功能中的新信号轴

基本信息

批准号：
10677738
负责人：
Aikaterini Kontrogianni-Konstantopoulos
金额：
$ 63.84万
依托单位：
UNIVERSITY OF MARYLAND BALTIMORE
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-08-05 至 2026-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10677738
关键词：
Address Adherens Junction Adhesions Affect Affinity Aging Aortic Valve Stenosis Arrhythmogenic Right Ventricular Dysplasia Binding Biochemical Biological Biological Assay Calmodulin Cardiac Cardiac Myocytes Cardiomyopathies Catalytic Domain Cell Communication Cell-Cell Adhesion Classification Communication Coupling Cytoplasmic Tail Cytoskeletal Proteins Development Dilated Cardiomyopathy Disease Dominant-Negative Mutation Electrophysiology (science)Family Fibronectins Gene Delivery Genes Health Heart Heart Abnormalities Heart Diseases Heart failure Human Immunoglobulins In Vitro Injections Intercalated disc Kinetics Knock-in Mouse Left ventricular non-compaction Link Mass Spectrum Analysis Mechanics Mediating Membrane Membrane Microdomains Missense Mutation Modeling Molecular Morphology Mus Mutagenesis Mutate Mutation Myocardium Myosin Light Chain Kinase N-Cadherin Normalcy Pathogenesis Pathogenicity Patients Phosphorylation Phosphotransferases Physiological Play Pre-Clinical Model Property Protein Isoforms Protein Truncation Proteins Role Sarcolemma Sequence Homology Signal Transduction Site Striated Muscles Structure Surface Plasmon Resonance Tachycardia Time Variant Viral Work cardiogenesis congenital heart disorder effective therapy in vivo member mouse model next generation sequencing novel novel therapeutics obscurin overexpression phosphoproteomics targeted treatment therapy development young adult

项目摘要

OBSCN encodes a family of giant, cytoskeletal proteins, obscurins, that play key structural and regulatory roles in striated muscles. Consistent with this, mutations in OBSCN have been associated with different forms of cardiomyopathies. Obscurin-B (~870 kDa), the largest known obscurin isoform is a modular protein consisting of immunoglobulin (Ig) and fibronectin-III (Fn-III) domains followed by an array of tandem signaling motifs and two COOH-terminal Ser/Thr kinase domains, Kin1 and Kin2 that share ~45% homology with Myosin Light Chain kinases. Although the presence of Kin1 and Kin2 was discovered almost two decades ago, their enzymatic activity, catalytic substrates and (patho)physiological roles have remained largely elusive. Recently, our group demonstrated that both Kin1 and Kin2 are enzymatically active. In particular, Kin1 undergoes autophospho- rylation and phosphorylates the cytoplasmic domain of N-cadherin. N-cadherin is an essential component of the adherens junctions (AJ) present in the intercalated disc (ICD), the unique microdomain of the sarcolemma that mediates the mechanical and electrical coupling of neighboring cardiomyocytes. In view of these findings and given the coincident distribution of obscurin-B containing Kin1 and N-cadherin at the ICD, we hypothesize that obscurin-Kin1 plays key roles in cardiomyocyte adhesion and/or communication (at least in part) by modulating the activities of N-cadherin via phosphorylation of its cytoplasmic domain. We will address this hypothesis by elucidating the molecular mechanisms that regulate Kin1 activation (Aim 1), determine the role of Kin1-mediated phosphorylation of N-cadherin in cardiac structure/function (Aim 2), and assessing the impact of a missense mutation in Kin1 linked to the development of dilated cardiomyopathy (DCM) in humans (Aim 3). During the last decade, mounting evidence has accumulated, highlighting the intimate involvement of obscurins in cardiac structure/function in health and the pathogenesis of heart disease when mutated or truncated. Moreover, the pivotal role of N-cadherin in the mechanical and electrical coupling of adjacent cardiomyocytes has been extensively documented, although the molecular mechanisms that regulate its functional properties have only been scantily examined. Our proposal is motivated by this view and will provide important information about the role of the novel obscurin-Kin1/N-cadherin signaling axis at the ICD in health and how it is compromised in disease. It will therefore address a fundamental biological question that has translational relevance.

obcn编码了一个巨大的细胞骨架蛋白家族，即扮演关键结构和调节角色的暗蛋白