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

Agnieszka Galińska, Victoria Hatch, Roger Craig, Anne M. Murphy, Jennifer Van Eyk, C. L.Albert Wang, William Lehman, D. Brian Foster

Research output: Contribution to journalArticlepeer-review


Rationale: Ca 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 (cTnI1-192) 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 Ca2+-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-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.

Original languageEnglish (US)
Pages (from-to)705-711
Number of pages7
JournalCirculation research
Issue number4
StatePublished - Mar 2010


  • Cardiomyopathy
  • Myocardial stunning
  • Thin filament
  • Troponin

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine


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