Functional and evolutionary relationships of troponin C

Abstract

ated muscle contraction is initiated when, following membrane depolarization, Ca 2ϩ binds to the low-affinity Ca 2ϩ binding sites of troponin C (TnC). The Ca 2ϩ activation of this protein results in a rearrangement of the components (troponin I, troponin T, and tropomyosin) of the thin filament, resulting in increased interaction between actin and myosin and the formation of cross bridges. The functional properties of this protein are therefore critical in determining the active properties of striated muscle. To date there are 61 known TnCs that have been cloned from 41 vertebrate and invertebrate species. In vertebrate species there are also distinct fast skeletal muscle and cardiac TnC proteins. While there is relatively high conservation of the amino acid sequence of TnC homologs between species and tissue types, there is wide variation in the functional properties of these proteins. To date there has been extensive study of the structure and function of this protein and how differences in these translate into the functional properties of muscles. The purpose of this work is to integrate these studies of TnC with phylogenetic analysis to investigate how changes in the sequence and function of this protein, integrate with the evolution of striated muscle. phylogenetic analysis; protein evolution; temperature; muscle TROPONIN C (TnC), present in all striated muscle, is the Ca 2ϩ -activated trigger that initiates myocyte contraction. The binding of Ca 2ϩ to TnC initiates a cascade of conformational changes through the component proteins of the thin filament, leading to the formation of cross bridges (CBs) between actin and myosin and the generation of force by the myocyte. Therefore, the functional properties of TnC, including its ability to be activated by Ca 2ϩ , have significant regulatory influence on the contractile reaction of the myocyte. Myocyte contractility is also influenced by the strength of interaction between actin and myosin, the rate of CB cycling, and the rate of ATP hydrolysis by myosin ATPase (24). There are two muscle-specific TnC proteins found in vertebrate striated muscle. The first, skeletal TnC (sTnC), is expressed in fast skeletal muscle and the second, cardiac TnC (cTnC), is expressed in cardiac and slow skeletal muscle. A critical difference between these two paralogs is that sTnC is activated by Ca 2ϩ binding to two low-affinity sites on the NH 2 terminus of the protein (sites I and II), while cTnC is activated by Ca 2ϩ binding to a single low-affinity site (site II). Site I is nonfunctional in cTnC due to sequence manipulations that have disrupted its ability to coordinate Ca 2ϩ ion binding. cTnC and sTnC have been cloned from a variety of vertebrate species across a range of phylogenic groups. The most ancient of these is the arctic lamprey, Lampetra japonica, a member of the earliest diverged vertebrate taxon. L. japonica sTnC and cTnC are 70 and 83% identical to human sTnC and cTnC, respectively. The presence of distinct cTnC and sTnC paralogs in L. japonica suggests that these ...

Breakpoint regions and homologous synteny blocks in chromosomes have different evolutionary histories

“…Genes belonging to four MetaCore process networks were enriched in the EBRs compared with their distribution in the whole genome (FDR <5%), three associated with inflammatory response and one with muscle contraction. Inflammatory responses and muscle contractility are both traits that involve an organism's response to external stimuli (Gillis et al 2007;Li and Flavell 2008). These results were supported by an independent analysis of GO terms that identified significant differences for the terms ''response to stimulus'' and ''immune system response'' (see Supplemental Table 4).…”

Quantifying inter‐species differences in contractile function through biophysical modelling

“…This is represented by the decrease in the unbinding rate of calcium to TnC with increasing active tension, which was much lower for mouse than for rat and human. This result was unexpected, as TnC sequences are known to be relatively consistent between species (Gillis et al 2007). This discrepancy between conserved TnC sequence and differences in kinetics may be explained by differences in troponin I (TnI) properties or phosphorylation level between species.…”

“…This translates into functional differences in the sarcomere and gives rise to inter-species differences in the resulting function (Gillis et al 2007). While there is relatively high conservation of the amino acid sequences of TnC homologues between species and tissue types, there is wide variation in the functional properties of these proteins (Gillis et al 2007). Moreover, regulatory proteins in the heart are potential targets for phosphorylation (Scruggs et al 2009).…”

DESIGN AND PHYSIOLOGY OF THE HEART | Cardiac Excitation–Contraction Coupling: Calcium and the Contractile Element

“…Means indicated with the same superscript are not significantly different from each other (p > 0.05). Adapted from Gillis TE, Marshall CR, and Tibbits GF (2007) Functional and evolutionary relationships of troponin C. Physiological Genomics 32: 16-27, used with permission from the American Physiological Socity.…”