TY - JOUR
T1 - Cardiac troponin T mutation R141W found in dilated cardiomyopathy stabilizes the troponin T-tropomyosin interaction and causes a Ca2+ desensitization
AU - Lu, Qun Wei
AU - Morimoto, Sachio
AU - Harada, Keita
AU - Du, Cheng Kun
AU - Takahashi-Yanaga, Fumi
AU - Miwa, Yoshikazu
AU - Sasaguri, Toshiyuki
AU - Ohtsuki, Iwao
N1 - Funding Information:
This study was supported by Special Coordination Funds from the Ministry of Education, Culture, Sports, Science and Technology of the Japanese Government.
PY - 2003/12
Y1 - 2003/12
N2 - A missense mutation R141W in the strong tropomyosin-binding region of cardiac troponin T (cTnT) has recently been reported to cause dilated cardiomyopathy (DCM), following the first report of a DCM-causing deletion mutation ΔK210. To clarify the molecular mechanism for the pathogenesis of DCM caused by this novel mutation in cTnT gene, functional analyses were made on the recombinant human cTnT mutant proteins. Exchanging human wild-type and mutant cTnTs into rabbit skinned cardiac muscle fibers revealed that R141W mutation resulted in a decrease in the Ca2+ sensitivity of force generation, as in the case of ΔK210 mutation lying outside the strong tropomyosin-binding region. In contrast, a missense mutation R94L in the vicinity of the strong tropomyosin-binding region associated with hypertrophic cardiomyopathy (HCM) resulted in an increase in the Ca2+ sensitivity of force generation, as in the case of the other HCM-causing mutations in cTnT reported previously. An assay using a quartz-crystal microbalance (a very sensitive mass-measuring device) revealed that R141W mutation increased the affinity of cTnT for α-tropomyosin by approximately three times, whereas an HCM-causing mutation ΔE160 in the strong tropomyosin-binding region, as well as ΔK210 and R94L mutations, had no effects on the interaction between cTnT and α-tropomyosin. Since cTnT has an important role in structurally integrating cardiac troponin I (cTnI) into the thin filaments via its two-way interactions with cTnI and tropomyosin, the present results suggest that R141W mutation in the strong tropomyosin-binding region in cTnT strengthens the integrity of cTnI in the thin filament by stabilizing the interaction between cTnT and tropomyosin, which might allow cTnI to inhibit the thin filament more effectively, leading to a Ca2+ desensitization.
AB - A missense mutation R141W in the strong tropomyosin-binding region of cardiac troponin T (cTnT) has recently been reported to cause dilated cardiomyopathy (DCM), following the first report of a DCM-causing deletion mutation ΔK210. To clarify the molecular mechanism for the pathogenesis of DCM caused by this novel mutation in cTnT gene, functional analyses were made on the recombinant human cTnT mutant proteins. Exchanging human wild-type and mutant cTnTs into rabbit skinned cardiac muscle fibers revealed that R141W mutation resulted in a decrease in the Ca2+ sensitivity of force generation, as in the case of ΔK210 mutation lying outside the strong tropomyosin-binding region. In contrast, a missense mutation R94L in the vicinity of the strong tropomyosin-binding region associated with hypertrophic cardiomyopathy (HCM) resulted in an increase in the Ca2+ sensitivity of force generation, as in the case of the other HCM-causing mutations in cTnT reported previously. An assay using a quartz-crystal microbalance (a very sensitive mass-measuring device) revealed that R141W mutation increased the affinity of cTnT for α-tropomyosin by approximately three times, whereas an HCM-causing mutation ΔE160 in the strong tropomyosin-binding region, as well as ΔK210 and R94L mutations, had no effects on the interaction between cTnT and α-tropomyosin. Since cTnT has an important role in structurally integrating cardiac troponin I (cTnI) into the thin filaments via its two-way interactions with cTnI and tropomyosin, the present results suggest that R141W mutation in the strong tropomyosin-binding region in cTnT strengthens the integrity of cTnI in the thin filament by stabilizing the interaction between cTnT and tropomyosin, which might allow cTnI to inhibit the thin filament more effectively, leading to a Ca2+ desensitization.
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U2 - 10.1016/j.yjmcc.2003.09.003
DO - 10.1016/j.yjmcc.2003.09.003
M3 - Article
C2 - 14654368
AN - SCOPUS:0344924880
VL - 35
SP - 1421
EP - 1427
JO - Journal of Molecular and Cellular Cardiology
JF - Journal of Molecular and Cellular Cardiology
SN - 0022-2828
IS - 12
ER -