Pathogenic peptide deviations support a model of adaptive evolution of chordate cardiac performance by troponin mutations

Palpant N.J., Houang E.M., Delport W., Hastings K.E.M., Onufriev A.V., Sham Y.Y. and Metzger J.M. (2010) Pathogenic peptide deviations support a model of adaptive evolution of chordate cardiac performance by troponin mutations. Physiological Genomics, 42 2: 287-299. doi:10.1152/physiolgenomics.00033.2010


Author Palpant N.J.
Houang E.M.
Delport W.
Hastings K.E.M.
Onufriev A.V.
Sham Y.Y.
Metzger J.M.
Title Pathogenic peptide deviations support a model of adaptive evolution of chordate cardiac performance by troponin mutations
Journal name Physiological Genomics   Check publisher's open access policy
ISSN 1094-8341
1531-2267
Publication date 2010-07-01
Year available 2010
Sub-type Article (original research)
DOI 10.1152/physiolgenomics.00033.2010
Open Access Status Not yet assessed
Volume 42
Issue 2
Start page 287
End page 299
Total pages 13
Place of publication Bethesda, United States
Publisher American Physiological Society
Language eng
Abstract In cardiac muscle, the troponin (cTn) complex is a key regulator of myofilament calcium sensitivity because it serves as a molecular switch required for translating myocyte calcium fluxes into sarcomeric contraction and relaxation. Studies of several species suggest that ectotherm chordates have myofilaments with heightened calcium responsiveness. However, genetic polymorphisms in cTn that cause increased myofilament sensitivity to activating calcium in mammals result in cardiac disease including arrhythmias, diastolic dysfunction, and increased susceptibility to sudden cardiac death. We hypothesized that specific residue modifications in the regulatory arm of troponin I (TnI) were critical in mediating the observed decrease in myofilament calcium sensitivity within the mammalian taxa. We performed large-scale phylogenetic analysis, atomic resolution molecular dynamics simulations and modeling, and computational alanine scanning. This study provides evidence that a His to Ala substitution within mammalian cardiac TnI (cTnI) reduced the thermodynamic potential at the interface between cTnI and cardiac TnC (cTnC) in the calcium-saturated state by disrupting a strong intermolecular electrostatic interaction. This key residue modification reduced myofilament calcium sensitivity by making cTnI molecularly untethered from cTnC. To meet the requirements for refined mammalian adult cardiac performance, we propose that compensatory evolutionary pressures favored mutations that enhanced the relaxation properties of cTn by decreasing its sensitivity to activating calcium.
Keyword Amphibian
Histidine
Mammal
Myofilament
Single nucleotide polymorphism
Q-Index Code C1
Q-Index Status Provisional Code
Grant ID RO1-HL-059301
0715632Z
Institutional Status Non-UQ

Document type: Journal Article
Sub-type: Article (original research)
Collection: Institute for Molecular Bioscience - Publications
 
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