Imperial College London
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ProfessorSteveMarston

Faculty of Medicine, National Heart & Lung Institute

Emeritus Professor
 
 
 
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Contact

 

+44 (0)20 7594 2732s.marston Website

 
 
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Location

 

433ICTEM buildingHammersmith Campus

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Summary

 

Publications

Citation

BibTex format

@article{Messer:2016:10.1016/j.abb.2016.03.027,
author = {Messer, A and Bayliss, C and El-Mezgueldi, M and Redwood, C and Ward, D and Leung, M and Papadaki, M and Remedios, C and Marston, SB},
doi = {10.1016/j.abb.2016.03.027},
journal = {Archives of Biochemistry and Biophysics},
pages = {113--120},
title = {Mutations in troponin T associated with Hypertrophic Cardiomyopathy increase Ca2+-sensitivity and suppress the modulation of Ca2+-sensitivity by troponin I phosphorylation},
url = {http://dx.doi.org/10.1016/j.abb.2016.03.027},
volume = {601},
year = {2016}
}
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RIS format (EndNote, RefMan)

TY  - JOUR
AB  - We investigated the effect of 7 Hypertrophic Cardiomyopathy (HCM)-causing mutations in troponin T (TnT) on troponin function in thinfilaments reconstituted with actin and human cardiac tropomyosin. Weused the quantitative in vitro motility assay to study Ca2+-regulation ofunloaded movement and its modulation by troponin I phosphorylation.Troponin from a patient with the K280N TnT mutation showed nodifference in Ca2+-sensitivity when compared with donor heart troponinand the Ca2+-sensitivity was also independent of the troponin Iphosphorylation level (uncoupled). The recombinant K280N TnT mutationincreased Ca2+-sensitivity 1.7-fold and was also uncoupled. The R92Q TnTmutation in troponin from transgenic mouse increased Ca2+-sensitivity andwas also completely uncoupled. Five TnT mutations (14, 28+7, E160,S179F and K273E) studied in recombinant troponin increased Ca2+-sensitivity and were all fully uncoupled. Thus, for HCM-causing mutationsin TnT, Ca2+-sensitisation together with uncoupling in vitro is the usualresponse and both factors may contribute to the HCM phenotype. We alsofound that Epigallocatechin-3-gallate (EGCG) can restore coupling to alluncoupled HCM-causing TnT mutations. In fact the combination of Ca2+-desensitisation and re-coupling due to EGCG completely reverses both theabnormalities found in troponin with a TnT HCM mutation suggesting itmay have therapeutic potential.
AU  - Messer,A
AU  - Bayliss,C
AU  - El-Mezgueldi,M
AU  - Redwood,C
AU  - Ward,D
AU  - Leung,M
AU  - Papadaki,M
AU  - Remedios,C
AU  - Marston,SB
DO  - 10.1016/j.abb.2016.03.027
EP  - 120
PY  - 2016///
SN  - 1096-0384
SP  - 113
TI  - Mutations in troponin T associated with Hypertrophic Cardiomyopathy increase Ca2+-sensitivity and suppress the modulation of Ca2+-sensitivity by troponin I phosphorylation
T2  - Archives of Biochemistry and Biophysics
UR  - http://dx.doi.org/10.1016/j.abb.2016.03.027
UR  - http://hdl.handle.net/10044/1/30972
VL  - 601
ER  -
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