The C terminus of cardiac troponin I stabilizes the Ca2+-activated state of tropomyosin on actin filaments

Circ Res. 2010 Mar 5;106(4):705-11. doi: 10.1161/CIRCRESAHA.109.210047. Epub 2009 Dec 24.


Rationale: Ca(2+) control of troponin-tropomyosin position on actin regulates cardiac muscle contraction. The inhibitory subunit of troponin, cardiac troponin (cTn)I is primarily responsible for maintaining a tropomyosin conformation that prevents crossbridge cycling. Despite extensive characterization of cTnI, the precise role of its C-terminal domain (residues 193 to 210) is unclear. Mutations within this region are associated with restrictive cardiomyopathy, and C-terminal deletion of cTnI, in some species, has been associated with myocardial stunning.

Objective: We sought to investigate the effect of a cTnI deletion-removal of 17 amino acids from the C terminus- on the structure of troponin-regulated tropomyosin bound to actin.

Methods and results: A truncated form of human cTnI (cTnI(1-192)) was expressed and reconstituted with troponin C and troponin T to form a mutant troponin. Using electron microscopy and 3D image reconstruction, we show that the mutant troponin perturbs the positional equilibrium dynamics of tropomyosin in the presence of Ca(2+). Specifically, it biases tropomyosin position toward an "enhanced C-state" that exposes more of the myosin-binding site on actin than found with wild-type troponin.

Conclusions: In addition to its well-established role of promoting the so-called "blocked-state" or "B-state," cTnI participates in proper stabilization of tropomyosin in the "Ca(2+)-activated state" or "C-state." The last 17 amino acids perform this stabilizing role. The data are consistent with a "fly-casting" model in which the mobile C terminus of cTnI ensures proper conformational switching of troponin-tropomyosin. Loss of actin-sensing function within this domain, by pathological proteolysis or cardiomyopathic mutation, may be sufficient to perturb tropomyosin conformation.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Actin Cytoskeleton / metabolism*
  • Actin Cytoskeleton / ultrastructure
  • Animals
  • Binding Sites
  • Calcium / metabolism*
  • Cattle
  • Humans
  • Imaging, Three-Dimensional
  • Microscopy, Electron
  • Models, Molecular
  • Multiprotein Complexes
  • Mutation
  • Myocardial Contraction*
  • Myocardium / metabolism*
  • Protein Conformation
  • Protein Structure, Tertiary
  • Rabbits
  • Recombinant Proteins / metabolism
  • Tropomyosin / metabolism*
  • Tropomyosin / ultrastructure
  • Troponin C / metabolism
  • Troponin I / genetics
  • Troponin I / metabolism*
  • Troponin I / ultrastructure
  • Troponin T / metabolism


  • Multiprotein Complexes
  • Recombinant Proteins
  • Tropomyosin
  • Troponin C
  • Troponin I
  • Troponin T
  • Calcium