| 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] [TNNI3_HUMAN] Defects in TNNI3 are the cause of familial hypertrophic cardiomyopathy type 7 (CMH7) [MIM:613690]. Familial hypertrophic cardiomyopathy is 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.[6] [7] [8] [9] [10] Defects in TNNI3 are the cause of familial restrictive cardiomyopathy type 1 (RCM1) [MIM:115210]. RCM1 is a heart muscle disorder characterized by impaired filling of the ventricles with reduced diastolic volume, in the presence of normal or near normal wall thickness and systolic function.[11] Defects in TNNI3 are the cause of cardiomyopathy dilated type 2A (CMD2A) [MIM:611880]. 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.[12] Defects in TNNI3 are the cause of cardiomyopathy dilated type 1FF (CMD1FF) [MIM:613286]. 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.
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. [TNNI3_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 PubMed
Intracellular acidosis lowers the Ca2+ sensitivity of cardiac muscle, which results in decreased force generation, decreased cardiac output, and, eventually, heart failure. The A162H mutant of cardiac troponin I in the thin filament turns the heart acidosis-resistant. Physiological and structural studies have provided insights into the mechanism of protection by the A162H substitution; however, the effect of other native residues of cardiac troponin I is not fully understood. In this study, we determined the structure of the A162H mutant of the switch region of cardiac troponin I bound to the regulatory domain of troponin C at pH 6.1, and the dynamics as a function of pH, by NMR spectroscopy to evaluate the changes induced by protonation of A162H. The results indicate that A162H induces a transitory curved conformation on troponin I that promotes contraction, but it is countered by residue E164 to ensure proper relaxation. Our model explains the absence of diastolic impairment in the gain-of-function phenotype induced by the A162H substitution as well as the effects of a variety of mutants studied previously. The description of this mechanism underlines the fine quality of regulation on cardiac muscle contraction and anticipates pharmacological agents that induce modest changes in the contraction-relaxation equilibrium to produce marked effects in cardiac performance.
Structure and Dynamics of the Acidosis-Resistant A162H Mutant of the Switch Region of Troponin I Bound to the Regulatory Domain of Troponin C.,Pineda-Sanabria SE, Robertson IM, Sykes BD Biochemistry. 2015 Jun 2. PMID:25996354[13]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ Mogensen J, Murphy RT, Shaw T, Bahl A, Redwood C, Watkins H, Burke M, Elliott PM, McKenna WJ. Severe disease expression of cardiac troponin C and T mutations in patients with idiopathic dilated cardiomyopathy. J Am Coll Cardiol. 2004 Nov 16;44(10):2033-40. PMID:15542288 doi:S0735-1097(04)01700-0
- ↑ Hoffmann B, Schmidt-Traub H, Perrot A, Osterziel KJ, Gessner R. First mutation in cardiac troponin C, L29Q, in a patient with hypertrophic cardiomyopathy. Hum Mutat. 2001 Jun;17(6):524. PMID:11385718 doi:10.1002/humu.1143
- ↑ Schmidtmann A, Lindow C, Villard S, Heuser A, Mugge A, Gessner R, Granier C, Jaquet K. Cardiac troponin C-L29Q, related to hypertrophic cardiomyopathy, hinders the transduction of the protein kinase A dependent phosphorylation signal from cardiac troponin I to C. FEBS J. 2005 Dec;272(23):6087-97. PMID:16302972 doi:10.1111/j.1742-4658.2005.05001.x
- ↑ Landstrom AP, Parvatiyar MS, Pinto JR, Marquardt ML, Bos JM, Tester DJ, Ommen SR, Potter JD, Ackerman MJ. Molecular and functional characterization of novel hypertrophic cardiomyopathy susceptibility mutations in TNNC1-encoded troponin C. J Mol Cell Cardiol. 2008 Aug;45(2):281-8. doi: 10.1016/j.yjmcc.2008.05.003. Epub , 2008 May 11. PMID:18572189 doi:10.1016/j.yjmcc.2008.05.003
- ↑ Pinto JR, Parvatiyar MS, Jones MA, Liang J, Ackerman MJ, Potter JD. A functional and structural study of troponin C mutations related to hypertrophic cardiomyopathy. J Biol Chem. 2009 Jul 10;284(28):19090-100. doi: 10.1074/jbc.M109.007021. Epub, 2009 May 12. PMID:19439414 doi:10.1074/jbc.M109.007021
- ↑ Kimura A, Harada H, Park JE, Nishi H, Satoh M, Takahashi M, Hiroi S, Sasaoka T, Ohbuchi N, Nakamura T, Koyanagi T, Hwang TH, Choo JA, Chung KS, Hasegawa A, Nagai R, Okazaki O, Nakamura H, Matsuzaki M, Sakamoto T, Toshima H, Koga Y, Imaizumi T, Sasazuki T. Mutations in the cardiac troponin I gene associated with hypertrophic cardiomyopathy. Nat Genet. 1997 Aug;16(4):379-82. PMID:9241277 doi:10.1038/ng0897-379
- ↑ Niimura H, Patton KK, McKenna WJ, Soults J, Maron BJ, Seidman JG, Seidman CE. Sarcomere protein gene mutations in hypertrophic cardiomyopathy of the elderly. Circulation. 2002 Jan 29;105(4):446-51. PMID:11815426
- ↑ Richard P, Charron P, Carrier L, Ledeuil C, Cheav T, Pichereau C, Benaiche A, Isnard R, Dubourg O, Burban M, Gueffet JP, Millaire A, Desnos M, Schwartz K, Hainque B, Komajda M. Hypertrophic cardiomyopathy: distribution of disease genes, spectrum of mutations, and implications for a molecular diagnosis strategy. Circulation. 2003 May 6;107(17):2227-32. Epub 2003 Apr 21. PMID:12707239 doi:10.1161/01.CIR.0000066323.15244.54
- ↑ Erdmann J, Daehmlow S, Wischke S, Senyuva M, Werner U, Raible J, Tanis N, Dyachenko S, Hummel M, Hetzer R, Regitz-Zagrosek V. Mutation spectrum in a large cohort of unrelated consecutive patients with hypertrophic cardiomyopathy. Clin Genet. 2003 Oct;64(4):339-49. PMID:12974739
- ↑ Ingles J, Doolan A, Chiu C, Seidman J, Seidman C, Semsarian C. Compound and double mutations in patients with hypertrophic cardiomyopathy: implications for genetic testing and counselling. J Med Genet. 2005 Oct;42(10):e59. PMID:16199542 doi:10.1136/jmg.2005.033886
- ↑ Mogensen J, Kubo T, Duque M, Uribe W, Shaw A, Murphy R, Gimeno JR, Elliott P, McKenna WJ. Idiopathic restrictive cardiomyopathy is part of the clinical expression of cardiac troponin I mutations. J Clin Invest. 2003 Jan;111(2):209-16. PMID:12531876 doi:10.1172/JCI16336
- ↑ Murphy RT, Mogensen J, Shaw A, Kubo T, Hughes S, McKenna WJ. Novel mutation in cardiac troponin I in recessive idiopathic dilated cardiomyopathy. Lancet. 2004 Jan 31;363(9406):371-2. PMID:15070570 doi:10.1016/S0140-6736(04)15468-8
- ↑ Pineda-Sanabria SE, Robertson IM, Sykes BD. Structure and Dynamics of the Acidosis-Resistant A162H Mutant of the Switch Region of Troponin I Bound to the Regulatory Domain of Troponin C. Biochemistry. 2015 Jun 2. PMID:25996354 doi:http://dx.doi.org/10.1021/acs.biochem.5b00178
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