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Enhanced troponin I binding explains the functional changes produced by the hypertrophic cardiomyopathy mutation A8V of cardiac troponin C.

Title: Enhanced troponin I binding explains the functional changes produced by the hypertrophic cardiomyopathy mutation A8V of cardiac troponin C.
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Name(s): Zot, Henry G, author
Hasbun, Javier E, author
Michell, Clara A, author
Landim-Vieira, Maicon, author
Pinto, Jose R, author
Type of Resource: text
Genre: Journal Article
Text
Date Issued: 2016-07-01
Physical Form: computer
online resource
Extent: 1 online resource
Language(s): English
Abstract/Description: Higher affinity for TnI explains how troponin C (TnC) carrying a causative hypertrophic cardiomyopathy mutation, TnC(A8V), sensitizes muscle cells to Ca(2+). Muscle fibers reconstituted with TnC(A8V) require ∼2.3-fold less [Ca(2+)] to achieve 50% maximum-tension compared to fibers reconstituted with wild-type TnC (TnC(WT)). Binding measurements rule out a significant change in N-terminus Ca(2+)-affinity of isolated TnC(A8V), and TnC(A8V) binds the switch-peptide of troponin-I (TnI(sp)) ∼1.6-fold more strongly than TnC(WT); thus we model the TnC-TnI(sp) interaction as competing with the TnI-actin interaction. Tension data are well-fit by a model constrained to conditions in which the affinity of TnC(A8V) for TnI(sp) is 1.5-1.7-fold higher than that of TnC(WT) at all [Ca(2+)]. Mean ATPase rates of reconstituted cardiac myofibrils is greater for TnC(A8V) than TnC(WT) at all [Ca(2+)], with statistically significant differences in the means at higher [Ca(2+)]. To probe TnC-TnI interaction in low Ca(2+), displacement of bis-ANS from TnI was monitored as a function of TnC. Whereas Ca(2+)-TnC(WT) displaces significantly more bis-ANS than Mg(2+)-TnC(WT), Ca(2+)-TnC(A8V) displaces probe equivalently to Mg(2+)-TnC(A8V) and Ca(2+)-TnC(WT), consistent with stronger Ca(2+)-independent TnC(A8V)-TnI(sp). A Matlab program for computing theoretical activation is reported. Our work suggests that contractility is constantly above normal in hearts made hypertrophic by TnC(A8V).
Identifier: FSU_pmch_26976709 (IID), 10.1016/j.abb.2016.03.011 (DOI), PMC4899184 (PMCID), 26976709 (RID), 26976709 (EID), S0003-9861(16)30063-7 (PII)
Keywords: Cardiac troponin C, Fluorescence, Hypertrophic cardiomyopathy, Modeling, Myofibrillar ATPase, Troponin I binding
Grant Number: K99 HL103840, R00 HL103840
Publication Note: This NIH-funded author manuscript originally appeared in PubMed Central at https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4899184.
Subject(s): Adenosine Triphosphatases/chemistry
Calcium/chemistry
Cardiomyopathy, Hypertrophic/genetics
Cardiomyopathy, Hypertrophic/metabolism
Humans
Imaging, Three-Dimensional
Microscopy, Fluorescence
Mutation
Myocardial Contraction
Myocardium/metabolism
Myofibrils/chemistry
Protein Binding
Protein Domains
Recombinant Proteins/chemistry
Troponin C/chemistry
Troponin C/genetics
Troponin I/chemistry
Troponin I/genetics
Persistent Link to This Record: http://purl.flvc.org/fsu/fd/FSU_pmch_26976709
Owner Institution: FSU
Is Part Of: Archives of biochemistry and biophysics.
1096-0384
Issue: vol. 601

Choose the citation style.
Zot, H. G., Hasbun, J. E., Michell, C. A., Landim-Vieira, M., & Pinto, J. R. (2016). Enhanced troponin I binding explains the functional changes produced by the hypertrophic cardiomyopathy mutation A8V of cardiac troponin C. Archives Of Biochemistry And Biophysics. Retrieved from http://purl.flvc.org/fsu/fd/FSU_pmch_26976709