2mkp
N domain of cardiac troponin C bound to the switch fragment of fast skeletal troponin I at pH 6N domain of cardiac troponin C bound to the switch fragment of fast skeletal troponin I at pH 6
Structural highlights
Disease[TNNC1_HUMAN] Defects in TNNC1 are the cause of cardiomyopathy dilated type 1Z (CMD1Z) [MIM:611879]. Dilated cardiomyopathy is a disorder characterized by ventricular dilation and impaired systolic function, resulting in congestive heart failure and arrhythmia. Patients are at risk of premature death.[1] Defects in TNNC1 are the cause of familial hypertrophic cardiomyopathy type 13 (CMH13) [MIM:613243]. A hereditary heart disorder characterized by ventricular hypertrophy, which is usually asymmetric and often involves the interventricular septum. The symptoms include dyspnea, syncope, collapse, palpitations, and chest pain. They can be readily provoked by exercise. The disorder has inter- and intrafamilial variability ranging from benign to malignant forms with high risk of cardiac failure and sudden cardiac death.[2] [3] [4] [5] [TNNI2_HUMAN] Sheldon-Hall syndrome;Digitotalar dysmorphism. The disease is caused by mutations affecting the gene represented in this entry. Function[TNNC1_HUMAN] Troponin is the central regulatory protein of striated muscle contraction. Tn consists of three components: Tn-I which is the inhibitor of actomyosin ATPase, Tn-T which contains the binding site for tropomyosin and Tn-C. The binding of calcium to Tn-C abolishes the inhibitory action of Tn on actin filaments. [TNNI2_HUMAN] Troponin I is the inhibitory subunit of troponin, the thin filament regulatory complex which confers calcium-sensitivity to striated muscle actomyosin ATPase activity. Publication Abstract from PubMedThe calcium sensitivity of cardiac and skeletal muscle is reduced during cytosolic acidosis, and this inhibition is more pronounced in cardiac muscle. Replacing cardiac troponin I with skeletal troponin I reduces the pH sensitivity of cardiac muscle. This diminished pH sensitivity depends on a single amino acid difference in troponin I: an alanine in cardiac and a histidine in skeletal. Studies suggested that when this histidine is protonated, it forms an electrostatic interaction with glutamate 19 on the surface of cardiac troponin C. Structures of the skeletal and cardiac troponin complexes show very different conformations for the region of troponin I surrounding this residue. In this study, we determined the structure of skeletal troponin I bound to cardiac troponin C. Skeletal troponin I is found to bind to cardiac troponin C with histidine 130 in close proximity to glutamate 19. This conformation is homologous to the crystal structure of the skeletal troponin complex; but different than in the cardiac complex. We show that an A162H variant of cardiac troponin I adopts a conformation similar to the skeletal structure. The implications of these structural differences in the context of cardiac muscle regulation are discussed. Conformation of the critical pH sensitive region of troponin depends upon a single residue in troponin I.,Robertson IM, Pineda-Sanabria SE, Holmes PC, Sykes BD Arch Biochem Biophys. 2013 Dec 12. pii: S0003-9861(13)00368-8. doi:, 10.1016/j.abb.2013.12.003. PMID:24333682[6] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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