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Amide Hydrogens Reveal A Temperature-dependent Structural Transition That Enhances Site-ii Ca2+ -binding Affinity In A C-domain Mutant Of Cardiac Troponin C

Title: Amide Hydrogens Reveal A Temperature-dependent Structural Transition That Enhances Site-ii Ca2+ -binding Affinity In A C-domain Mutant Of Cardiac Troponin C.
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Name(s): Veltri, Tiago, author
de Oliveira, Guilherme A. P., author
Bienkiewicz, Ewa A., author
Palhano, Fernando L., author
Marques, Mayra de A., author
Moraes, Adolfo H., author
Silva, Jerson L., author
Sorenson, Martha M., author
Pinto, Jose R., author
Type of Resource: text
Genre: Journal Article
Text
Journal Article
Date Issued: 2017-04-06
Physical Form: computer
online resource
Extent: 1 online resource
Language(s): English
Abstract/Description: The hypertrophic cardiomyopathy-associated mutant D145E, in cardiac troponin C (cTnC) C-domain, causes generalised instability at multiple sites in the isolated protein. As a result, structure and function of the mutant are more susceptible to higher temperatures. Above 25 degrees C there are large, progressive increases in N-domain Ca2+-binding affinity for D145E but only small changes for the wild-type protein. NMR-derived backbone amide temperature coefficients for many residues show a sharp transition above 30-40 degrees C, indicating a temperature-dependent conformational change that is most prominent around the mutated EF-hand IV, as well as throughout the C-domain. Smaller, isolated changes occur in the N-domain. Cardiac skinned fibres reconstituted with D145E are more sensitive to Ca2+ than fibres reconstituted with wild-type, and this defect is amplified near body-temperature. We speculate that the D145E mutation destabilises the native conformation of EF-hand IV, leading to a transient unfolding and dissociation of helix H that becomes more prominent at higher temperatures. This creates exposed hydrophobic surfaces that may be capable of binding unnaturally to a variety of targets, possibly including the N-domain of cTnC when it is in its open Ca2+-saturated state. This would constitute a potential route for propagating signals from one end of TnC to the other.
Identifier: FSU_libsubv1_wos_000398545900010 (IID), 10.1038/s41598-017-00777-6 (DOI)
Keywords: skeletal-muscle, hypertrophic cardiomyopathy, high-pressure, calcium-binding, chemical-shift index, n-domain, nmr-spectroscopy, protein secondary structure, regulatory domain, skinned ventricular-muscle
Publication Note: The publisher's version of record is available at https://doi.org/10.1038/s41598-017-00777-6
Persistent Link to This Record: http://purl.flvc.org/fsu/fd/FSU_libsubv1_wos_000398545900010
Owner Institution: FSU
Is Part Of: Scientific Reports.
2045-2322
Issue: vol. 7

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Veltri, T., De Oliveira, G. A. P., Bienkiewicz, E. A., Palhano, F. L., Marques, M. de A., Moraes, A. H., … Pinto, J. R. (2017). Amide Hydrogens Reveal A Temperature-dependent Structural Transition That Enhances Site-ii Ca2+ -binding Affinity In A C-domain Mutant Of Cardiac Troponin C. Scientific Reports. Retrieved from http://purl.flvc.org/fsu/fd/FSU_libsubv1_wos_000398545900010