Drastic Ca2+ sensitization of myofilament associated with a small structural change in troponin I in inherited restrictive cardiomyopathy

Fumiaki Yumoto, Qun Wei Lu, Sachio Morimoto, Hiroyuki Tanaka, Naoko Kono, Koji Nagata, Takao Ojima, Fumi Takahashi-Yanaga, Yoshikazu Miwa, Toshiyuki Sasaguri, Kiyoyoshi Nishita, Masaru Tanokura, Iwao Ohtsuki

Research output: Contribution to journalArticle

59 Citations (Scopus)

Abstract

Six missense mutations in human cardiac troponin I (cTnI) were recently found to cause restrictive cardiomyopathy (RCM). We have bacterially expressed and purified these human cTnI mutants and examined their functional and structural consequences. Inserting the human cTnI into skinned cardiac muscle fibers showed that these mutations had much greater Ca2+-sensitizing effects on force generation than the cTnI mutations in hypertrophic cardiomyopathy (HCM). The mutation K178E in the second actin-tropomyosin (Tm) binding region showed a particularly potent Ca2+-sensitizing effect among the six RCM-causing mutations. Circular dichroism and nuclear magnetic resonance spectroscopy revealed that this mutation does not extensively affect the structure of the whole cTnI molecule, but induces an unexpectedly subtle change in the structure of a region around the mutated residue. The results indicate that the K178E mutation has a localized effect on a structure that is critical to the regulatory function of the second actin-Tm binding region of cTnI. The present study also suggests that both HCM and RCM involving cTnI mutations share a common feature of increased Ca2+ sensitivity of cardiac myofilament, but more severe change in Ca2+ sensitivity is associated with the clinical phenotype of RCM.

Original languageEnglish
Pages (from-to)1519-1526
Number of pages8
JournalBiochemical and Biophysical Research Communications
Volume338
Issue number3
DOIs
Publication statusPublished - Dec 23 2005

    Fingerprint

All Science Journal Classification (ASJC) codes

  • Biophysics
  • Biochemistry
  • Molecular Biology
  • Cell Biology

Cite this