title: Pathogenic peptide deviations support a model of adaptive evolution of chordate cardiac performance by troponin mutations.
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.
authors.affiliation: Department of Integrative Biology and Physiology, University of Minnesota Academic Health Center, 321 Church Street SE, Minneapolis, MN 55455, USA.
authors.forename: Nathan J
authors.initials: NJ
authors.lastname: Palpant
authors.forename: Evelyne M
authors.initials: EM
authors.lastname: Houang
authors.forename: Wayne
authors.initials: W
authors.lastname: Delport
authors.forename: Kenneth E M
authors.initials: KE
authors.lastname: Hastings
authors.forename: Alexey V
authors.initials: AV
authors.lastname: Onufriev
authors.forename: Yuk Y
authors.initials: YY
authors.lastname: Sham
authors.forename: Joseph M
authors.initials: JM
authors.lastname: Metzger
mesh_terms: D000818:Animals; D002118:Calcium / Q000378:metabolism; D043344:Chordata / Q000235:genetics / Q000378:metabolism; D019143:Evolution, Molecular; D006801:Humans; D008958:Models, Molecular; D056004:Molecular Dynamics Simulation; D009154:Mutation; D010455:Peptides / Q000235:genetics; D010802:Phylogeny; D014336:Troponin / Q000235:genetics*; D019210:Troponin I / Q000737:chemistry / Q000235:genetics / Q000378:metabolism
chemical_list: D010455:Peptides; D014336:Troponin; D019210:Troponin I; D002118:Calcium