The missing links within troponin

Abstract

The cardiac contraction-relaxation cycle is controlled by a sophisticated set of machinery. Of particular interest, is the revelation that allosteric networks transmit effects of binding at one site to influence troponin complex dynamics and structural-mediated signaling in often distal, functional sites in the myofilament. Our recent observations provide compelling evidence that allostery can explain the function of large-scale macromolecular events. Here we elaborate on our recent findings of interdomain communication within troponin C, using cutting-edge structural biology approaches, and highlight the importance of unveiling the unknown, distant communication networks within this system to obtain more comprehensive knowledge of how allostery impacts cardiac physiology and disease.

Keywords: Allostery; Dynamics; Structural biology; Thin filament; Troponin.

Figure 1.. Schematics showing structural organization of TFs.

The density map of F-actin-Tm (EMDB code 8162), atomic models of F-actin-Tm (PDB code 5j1f), and cTn (PDB code 1j1e) were fit as rigid bodies and may not represent real positioning of cTn within TFs. The residues participating on Ca²⁺-binding at sites II and IV are shown as sticks and Ca²⁺ ions are indicated as green spheres. cTnC helices (αN-αH) are labeled within rectangles.

Figure 2.. Conserved motifs and allosteric elements within TnC.

(a) Conserved motif distribution within human cTnC (PDB code 1J1E). The percentage of sequence conservation are colored from red to blue. (b) Alignment of 38 skeletal and cTnC sequences from different organisms used to generate the conservation map in (a). Non-similar residues are colored in white/black; Conserved residues are cyan/blue; Strongly similar are green/black; Identical residues are indicated as yellow/red; Weakly similar residues are shown as white/green. Similarity is based upon the residues physicochemical properties. (c) Schematics showing new allosteric elements captured in our studies using the D145E mutant. Hydrogen bonds are shown as white dotted lines and residues presenting distinct H-bond patterns are shown in magenta. Water molecules are labeled as red/white spheres and Ca²⁺ ions as green spheres.