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Allosteric Transmission along a Loosely Structured Backbone Allows a Cardiac Troponin C Mutant to Function with Only One Ca Ion.

Title: Allosteric Transmission along a Loosely Structured Backbone Allows a Cardiac Troponin C Mutant to Function with Only One Ca Ion.
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Name(s): Marques, Mayra de A, author
Pinto, Jose Renato, author
Moraes, Adolfo H, author
Iqbal, Anwar, author
de Magalhães, Mariana T Q, author
Monteiro, Jamila, author
Pedrote, Murilo M, author
Sorenson, Martha M, author
Silva, Jerson L, author
de Oliveira, Guilherme A P, author
Type of Resource: text
Genre: Journal Article
Text
Date Issued: 2017-02-10
Physical Form: computer
online resource
Extent: 1 online resource
Language(s): English
Abstract/Description: Hypertrophic cardiomyopathy (HCM) is one of the most common cardiomyopathies and a major cause of sudden death in young athletes. The Ca sensor of the sarcomere, cardiac troponin C (cTnC), plays an important role in regulating muscle contraction. Although several cardiomyopathy-causing mutations have been identified in cTnC, the limited information about their structural defects has been mapped to the HCM phenotype. Here, we used high-resolution electron-spray ionization mass spectrometry (ESI-MS), Carr-Purcell-Meiboom-Gill relaxation dispersion (CPMG-RD), and affinity measurements of cTnC for the thin filament in reconstituted papillary muscles to provide evidence of an allosteric mechanism in mutant cTnC that may play a role to the HCM phenotype. We showed that the D145E mutation leads to altered dynamics on a μs-ms time scale and deactivates both of the divalent cation-binding sites of the cTnC C-domain. CPMG-RD captured a low populated protein-folding conformation triggered by the Glu-145 replacement of Asp. Paradoxically, although D145E C-domain was unable to bind Ca, these changes along its backbone allowed it to attach more firmly to thin filaments than the wild-type isoform, providing evidence for an allosteric response of the Ca-binding site II in the N-domain. Our findings explain how the effects of an HCM mutation in the C-domain reflect up into the N-domain to cause an increase of Ca affinity in site II, thus opening up new insights into the HCM phenotype.
Identifier: FSU_pmch_28049727 (IID), 10.1074/jbc.M116.765362 (DOI), PMC5313108 (PMCID), 28049727 (RID), 28049727 (EID), M116.765362 (PII)
Keywords: Calcium-binding protein, Cardiomyopathy, Nuclear magnetic resonance (NMR), Protein structure, Small-angle X-ray scattering (SAXS), Troponin
Grant Number: R01 HL128683
Publication Note: This NIH-funded author manuscript originally appeared in PubMed Central at https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5313108.
Subject(s): Allosteric Regulation
Animals
Cardiomyopathy, Hypertrophic/metabolism
Electrophoresis, Polyacrylamide Gel
Humans
Hydrophobic and Hydrophilic Interactions
Mutation
Myocardium/metabolism
Protein Conformation
Rats
Rats, Wistar
Spectrum Analysis/methods
Troponin C/chemistry
Troponin C/genetics
Troponin C/metabolism
Persistent Link to This Record: http://purl.flvc.org/fsu/fd/FSU_pmch_28049727
Owner Institution: FSU
Is Part Of: The Journal of biological chemistry.
1083-351X
Issue: iss. 6, vol. 292

Choose the citation style.
Marques, M. de A., Pinto, J. R., Moraes, A. H., Iqbal, A., De Magalhães, M. T. Q., Monteiro, J., … De Oliveira, G. A. P. (2017). Allosteric Transmission along a Loosely Structured Backbone Allows a Cardiac Troponin C Mutant to Function with Only One Ca Ion. The Journal Of Biological Chemistry. Retrieved from http://purl.flvc.org/fsu/fd/FSU_pmch_28049727