pH-responsive titratable inotropic performance of histidine-modified cardiac troponin i

Palpant, Nathan J., Houang, Evelyne M., Sham, Yuk Y. and Metzger, Joseph M. (2012) pH-responsive titratable inotropic performance of histidine-modified cardiac troponin i. Biophysical Journal, 102 7: 1570-1579. doi:10.1016/j.bpj.2012.01.024


Author Palpant, Nathan J.
Houang, Evelyne M.
Sham, Yuk Y.
Metzger, Joseph M.
Title pH-responsive titratable inotropic performance of histidine-modified cardiac troponin i
Journal name Biophysical Journal   Check publisher's open access policy
ISSN 0006-3495
1542-0086
Publication date 2012-04-04
Year available 2012
Sub-type Article (original research)
DOI 10.1016/j.bpj.2012.01.024
Open Access Status Not yet assessed
Volume 102
Issue 7
Start page 1570
End page 1579
Total pages 10
Place of publication St. Louis, MO United States
Publisher Cell Press
Language eng
Abstract Cardiac troponin I (cTnI) functions as the molecular switch of the thin filament. Studies have shown that a histidine button engineered into cTnI (cTnI A164H) specifically enhances inotropic function in the context of numerous pathophysiological challenges. To gain mechanistic insight into the basis of this finding, we analyzed histidine ionization states in vitro by studying the myofilament biophysics of amino acid substitutions that act as constitutive chemical mimetics of altered histidine ionization. We also assessed the role of histidine-modified cTnI in silico by means of molecular dynamics simulations. A functional in vitro analysis of myocytes at baseline (pH 7.4) indicated similar cellular contractile function and myofilament calcium sensitivity between myocytes expressing wild-type (WT) cTnI and cTnI A164H, whereas the A164R variant showed increased myofilament calcium sensitivity. Under acidic conditions, compared with WT myocytes, the myocytes expressing cTnI A164H maintained a contractile performance similar to that observed for the constitutively protonated cTnI A164R variant. Molecular dynamics simulations showed similar intermolecular atomic contacts between the WT and the deprotonated cTnI A164H variant. In contrast, simulations of protonated cTnI A164H showed various potential structural configurations, one of which included a salt bridge between His-164 of cTnI and Glu-19 of cTnC. This salt bridge was recapitulated in simulations of the cTnI A164R variant. These data suggest that differential histidine ionization may be necessary for cTnI A164H to act as a molecular sensor capable of modulating sarcomere performance in response to changes in the cytosolic milieu.
Keyword Biophysics
Biophysics
BIOPHYSICS
Q-Index Code C1
Q-Index Status Provisional Code
Institutional Status Non-UQ

Document type: Journal Article
Sub-type: Article (original research)
Collection: Institute for Molecular Bioscience - Publications
 
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Created: Tue, 30 Aug 2016, 20:57:26 EST by Anthony Yeates on behalf of Institute for Molecular Bioscience