Myofilament Calcium Sensitivity: Consequences of the Effective Concentration of Troponin I.

Jalal K Siddiqui,Svetlana B Tikunova,Shane D Walton,Bin Liu,Meredith Meyer,Nathan Neilson,Paul M L Janssen,Hussam E Salhi,Brandon J Biesiadecki,Pieter P De Tombe,Peter M Kekenes-Huskey,Jonathan P Davis

doi:10.3389/fphys.2016.00632

Jalal K Siddiqui, Svetlana B Tikunova + Show 10 more

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https://doi.org/10.3389/fphys.2016.00632

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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.

Highlights

The Ca2+ sensitivity of cardiac muscle contraction is compromised by many genetic and acquired cardiomyopathies (Hamdani et al, 2008; Tardiff, 2011; Liu et al, 2012a,b)
One of the striking and consistent findings across the literature is that the apparent Ca2+ binding properties of cardiac troponin C (TnC) vary substantially when studied in different systems
The apparent Ca2+ sensitivity is the lowest when only the isolated TnC is investigated, intermediate when the Tn complex is reconstituted onto the thin filament and highest in the isolated Tn complex or when the thin filament is bound by rigor myosin heads either in reconstituted thin filaments or Tn exchanged myofibrils

Summary

Introduction

The Ca2+ sensitivity of cardiac muscle contraction is compromised by many genetic and acquired cardiomyopathies (Hamdani et al, 2008; Tardiff, 2011; Liu et al, 2012a,b). Modeling TnC-TnI Interactions therapy does not lead to disease and can be utilized to protect and therapeutically aid the heart in a murine model of myocardial infarction (Shettigar et al, 2016). Consistent with these findings, not all disease associated mutations that alter the Ca2+ sensitivity of cardiac muscle have complete penetrance (Tardiff, 2011; Ploski et al, 2016).

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