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dc.contributor.authorHenze, Marcus
dc.contributor.authorPatrick, Stacey E.
dc.contributor.authorHinken, Aaron
dc.contributor.authorScruggs, Sarah B.
dc.contributor.authorGoldspink, Paul
dc.contributor.authorde Tombe, Pieter P.
dc.contributor.authorKobayashi, Minae
dc.contributor.authorPing, Peipei
dc.contributor.authorKobayashi, Tomoyoshi
dc.contributor.authorSolaro, R. John
dc.date.accessioned2013-11-19T19:42:24Z
dc.date.available2013-11-19T19:42:24Z
dc.date.issued2013-04
dc.identifier.bibliographicCitationHenze M, Patrick SE, Hinken A, Scruggs SB, Goldspink P, de Tombe PP, Kobayashi M, Ping P, Kobayashi T, Solaro RJ. New insights into the functional significance of the acidic region of the unique N-terminal extension of cardiac troponin I.BBA - Biochimica et Biophysica Acta . 2012 Aug 25. doi:pii: S0167-4889(12)00236-4. 10.1016/j.bbamcr.2012.08.012en_US
dc.identifier.issn0006-3002
dc.identifier.urihttp://hdl.handle.net/10027/10545
dc.descriptionNOTICE: This is the author’s version of a work that was accepted for publication in BBA - Biochimica et Biophysica Acta . Changes resulting from the publishing process, such as peer review, editing, corrections, structural formatting, and other quality control mechanisms may not be reflected in this document. Changes may have been made to this work since it was submitted for publication. A definitive version was subsequently published in BBA - Biochimica et Biophysica Acta ,(2012) DOI: 10.1016/j.bbamcr.2012.08.012en_US
dc.description.abstractPrevious structural studies indicated a special functional role for an acidic region composed of residues 1-10 in the unique N-terminal peptide of cardiac troponin I (cTnI). Employing LC-MS/MS, we determined the presence of phosphorylation sites at S5/S6 in cTnI from wild type mouse hearts as well as in hearts of mice chronically expressing active protein kinase C-ε (PKCε) and exhibiting severe dilated cardiomyopathy (DCM). To determine the functional significance of these phosphorylations, we cloned and expressed wild-type cTnI, (Wt), and cTnI variants expressing pseudo-phosphorylation cTnI-(S5D), cTnI(S6D), as well as cTnI(S5A) and cTnI(S6A). We exchanged native Tn of detergent-extracted (skinned) fiber bundles with Tn reconstituted with the variant cTnIs and measured tension and cross-bridge dynamics. Compared to controls, myofilaments controlled by cTnI with pseudo-phosphorylation (S6D) or Ala substitution (S6A) demonstrated a significant depression in maximum tension, ATPase rate, and k(tr), but no change in half-maximally activating Ca(2+). In contrast, pseudo-phosphorylation at position 5 (S5D) had no effects, although S5A induced an increase in Ca(2+)-sensitivity with no change in maximum tension or k(tr). We further tested the impact of acidic domain modifications on myofilament function in studies examining the effects of cTnI(A2V), a mutation linked to DCM. This mutation significantly altered the inhibitory activity of cTnI as well as cooperativity of activation of myofilament tension, but not when S23/S24 were pseudo-phosphorylated. Our data indicate a new functional and pathological role of amino acid modifications in the N-terminal acidic domain of cTnI that is modified by phosphorylations at cTnI(S23/S24). This article is part of a Special Issue entitled: Cardiomyocyte Biology: Cardiac Pathways of Differentiation, Metabolism and Contraction.en_US
dc.language.isoen_USen_US
dc.publisherElsevieren_US
dc.titleNew Insights Into the Functional Significance of the Acidic Region of the Unique NTerminal Extension of Cardiac Troponin Ien_US
dc.typeArticleen_US


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