title: Myofilament Calcium Sensitivity: Consequences of the Effective Concentration of Troponin I.
abstract: Control of calcium binding to and dissociation from cardiac troponin C (TnC) is essential to healthy cardiac muscle contraction/relaxation. There are numerous aberrant post-translational modifications and mutations within a plethora of contractile, and even non-contractile, proteins that appear to imbalance this delicate relationship. The direction and extent of the resulting change in calcium sensitivity is thought to drive the heart toward one type of disease or another. There are a number of molecular mechanisms that may be responsible for the altered calcium binding properties of TnC, potentially the most significant being the ability of the regulatory domain of TnC to bind the switch peptide region of TnI. Considering TnI is essentially tethered to TnC and cannot diffuse away in the absence of calcium, we suggest that the apparent calcium binding properties of TnC are highly dependent upon an "effective concentration" of TnI available to bind TnC. Based on our previous work, TnI peptide binding studies and the calcium binding properties of chimeric TnC-TnI fusion constructs, and building upon the concept of effective concentration, we have developed a mathematical model that can simulate the steady-state and kinetic calcium binding properties of a wide assortment of disease-related and post-translational protein modifications in the isolated troponin complex and reconstituted thin filament. We predict that several TnI and TnT modifications do not alter any of the intrinsic calcium or TnI binding constants of TnC, but rather alter the ability of TnC to "find" TnI in the presence of calcium. These studies demonstrate the apparent consequences of the effective TnI concentration in modulating the calcium binding properties of TnC.
authors.affiliation: Department of Physiology and Cell Biology and the Davis Heart and Lung Research Institute, The Ohio State University Columbus, OH, USA.
authors.forename: Jalal K
authors.initials: JK
authors.lastname: Siddiqui
authors.affiliation: Department of Physiology and Cell Biology and the Davis Heart and Lung Research Institute, The Ohio State University Columbus, OH, USA.
authors.forename: Svetlana B
authors.initials: SB
authors.lastname: Tikunova
authors.affiliation: Department of Physiology and Cell Biology and the Davis Heart and Lung Research Institute, The Ohio State University Columbus, OH, USA.
authors.forename: Shane D
authors.initials: SD
authors.lastname: Walton
authors.affiliation: Department of Physiology and Cell Biology and the Davis Heart and Lung Research Institute, The Ohio State University Columbus, OH, USA.
authors.forename: Bin
authors.initials: B
authors.lastname: Liu
authors.affiliation: Department of Physiology and Cell Biology and the Davis Heart and Lung Research Institute, The Ohio State University Columbus, OH, USA.
authors.forename: Meredith
authors.initials: M
authors.lastname: Meyer
authors.affiliation: Cell and Molecular Physiology, Loyola University Chicago Maywood, IL, USA.
authors.forename: Pieter P
authors.initials: PP
authors.lastname: de Tombe
authors.affiliation: Department of Physiology and Cell Biology and the Davis Heart and Lung Research Institute, The Ohio State University Columbus, OH, USA.
authors.forename: Nathan
authors.initials: N
authors.lastname: Neilson
authors.affiliation: Department of Chemistry, University of Kentucky Lexington, KY, USA.
authors.forename: Peter M
authors.initials: PM
authors.lastname: Kekenes-Huskey
authors.affiliation: Department of Physiology and Cell Biology and the Davis Heart and Lung Research Institute, The Ohio State University Columbus, OH, USA.
authors.forename: Hussam E
authors.initials: HE
authors.lastname: Salhi
authors.affiliation: Department of Physiology and Cell Biology and the Davis Heart and Lung Research Institute, The Ohio State University Columbus, OH, USA.
authors.forename: Paul M L
authors.initials: PM
authors.lastname: Janssen
authors.affiliation: Department of Physiology and Cell Biology and the Davis Heart and Lung Research Institute, The Ohio State University Columbus, OH, USA.
authors.forename: Brandon J
authors.initials: BJ
authors.lastname: Biesiadecki
authors.affiliation: Department of Physiology and Cell Biology and the Davis Heart and Lung Research Institute, The Ohio State University Columbus, OH, USA.
authors.forename: Jonathan P
authors.initials: JP
authors.lastname: Davis
keywords: effective concentration; mathematical model; thin filament; troponin C; troponin I