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|Title:||Mutations in troponin T associated with Hypertrophic Cardiomyopathy increase Ca²⁺-sensitivity and suppress the modulation of Ca²⁺-sensitivity by troponin I phosphorylation|
|Authors:||Messer, Andrew E.|
Bayliss, Christopher R.
Redwood, Charles S.
Ward, Douglas G.
Dos Remedios, Cristobal
Marston, Steven B.
|Citation:||Archives of Biochemistry and Biophysics, 2016, 601, pp. 113-120|
|Abstract:||We investigated the effect of 7 Hypertrophic Cardiomyopathy (HCM)-causing mutations in troponin T (TnT) on troponin function in thin filaments reconstituted with actin and human cardiac tropomyosin. We used the quantitative in vitro motility assay to study Ca²⁺-regulation of unloaded movement and its modulation by troponin I phosphorylation. Troponin from a patient with the K280N TnT mutation showed no difference in Ca²⁺-sensitivity when compared with donor heart troponin and the Ca²⁺-sensitivity was also independent of the troponin I phosphorylation level (uncoupled). The recombinant K280N TnT mutation increased Ca²⁺-sensitivity 1.7-fold and was also uncoupled. The R92Q TnT mutation in troponin from transgenic mouse increased Ca²⁺-sensitivity and was also completely uncoupled. Five TnT mutations (Δ14, Δ28 + 7, ΔE160, S179F and K273E) studied in recombinant troponin increased Ca2+-sensitivity and were all fully uncoupled. Thus, for HCM-causing mutations in TnT, Ca²⁺-sensitisation together with uncoupling in vitro is the usual response and both factors may contribute to the HCM phenotype. We also found that Epigallocatechin-3-gallate (EGCG) can restore coupling to all uncoupled HCM-causing TnT mutations. In fact the combination of Ca²⁺-desensitisation and re-coupling due to EGCG completely reverses both the abnormalities found in troponin with a TnT HCM mutation suggesting it may have therapeutic potential.|
|Rights:||Copyright © the authors, 2016. This is an open-access article distributed under the terms of the Creative Commons Attribution-Non Commercial-No Derivatives License (http://creativecommons.org/licenses/by-nc-nd/4.0/), which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made.|
|Appears in Collections:||Published Articles, Dept. of Molecular and Cell Biology|
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