Biophysical Derangements in Genetic Cardiomyopathies

Abstract

This article focuses on three "bins" that comprise sets of biophysical derangements elicited by cardiomyopathy-associated mutations in the myofilament. Current therapies focus on symptom palliation and do not address the disease at its core. We and others have proposed that a more nuanced classification could lead to direct interventions based on early dysregulation changing the trajectory of disease progression in the preclinical cohort. Continued research is necessary to address the complexity of cardiomyopathic progression and develop efficacious therapeutics.

Keywords: Calcium signaling; Cardiomyopathies; Phosphorylation potential; Primary; Protein stability; Therapeutics.

Figure 1:

Summary of cardiomyopathic disease progression and proposed “binning”. Dashed line represents the unknown time-course of disease progression between early dysregulation and ventricular remodeling.

Figure 2:

A - Atomistic Model of the cTnI-cTnC Interface generated from the publicly available average structure by JR Exequiel Pineda [1]. cTnI (dark blue), cTnC (red), cTnT (yellow). Dark vs light areas of the protein indicate spatial depth ie: near and far, respectively. cTnT is intentionally faded for clarity. Mutation sites discussed (cTnI R21 and R145, and cTnC G159) are marked with green beads, cTnI Ser22/23 are highlighted with cyan beads, and the active calcium binding pocket is marked with a grey bead. B – 2D representation of the interface, including the structural rearrangement upon PKA phosphorylation.

Figure 3:

Calcium Homeostasis and Dysregulation. L-type calcium channel (LTCC), Ryanodine Receptor (RyR), Sarcoplasmic Reticulum (SR), SR-bound calcium ATP-ase (SERCA), plasma membrane calcium ATP-ase (PMCA). Blue stars indicate current and proposed sites of therapeutic intervention for modulation of calcium homeostasis.

Figure 4:

Tm-Overlap Flexibility including the proposed “tolerance zone”. The semi-flexible Tm-overlap can vary within this zone (dotted line), becoming more (purple) or less (blue) flexible, outside of which is associated with disease. Overlaid on the gradient is the atomistic model generated from the publicly available average structure, by JR Exequiel Pineda, of the Tm N-terminus (orange), Tm C-terminus (green), and the N-terminal extension of cTnT (yellow) [1]. The arrows represent decreased (purple) or increased (blue) interaction of the five-helix bundle that comprises the Tm-overlap. Included on the Tm and cTnT model are the sites of the discussed mutations (Tm-D175, E180, L185, E62, E40, E54, D84, D230; cTnT R92) with HCM in red and DCM in dark blue.