TY - JOUR
T1 - Distortion of the Actin A-Triad Results in Contractile Disinhibition and Cardiomyopathy
AU - Viswanathan, Meera C.
AU - Schmidt, William
AU - Rynkiewicz, Michael J.
AU - Agarwal, Karuna
AU - Gao, Jian
AU - Katz, Joseph
AU - Lehman, William
AU - Cammarato, Anthony
N1 - Funding Information:
The authors thank Drs. Marek Orzechowski (Boston University School of Medicine) for preliminary molecular dynamics simulations and Aditi Madan (Johns Hopkins University) for technical assistance. This work was supported by NSF CBET-1438203 (to J.K.), ONR N000141512404 (to J.K.), and NIH grants T32HL007227-38 (to W.S.), R37HL036153 (to W.L.), R56HL124091 (to A.C.), and R01HL124091 (to A.C.).
Publisher Copyright:
© 2017 The Authors
PY - 2017/9/12
Y1 - 2017/9/12
N2 - Striated muscle contraction is regulated by the movement of tropomyosin over the thin filament surface, which blocks or exposes myosin binding sites on actin. Findings suggest that electrostatic contacts, particularly those between K326, K328, and R147 on actin and tropomyosin, establish an energetically favorable F-actin-tropomyosin configuration, with tropomyosin positioned in a location that impedes actomyosin associations and promotes relaxation. Here, we provide data that directly support a vital role for these actin residues, termed the A-triad, in tropomyosin positioning in intact functioning muscle. By examining the effects of an A295S α-cardiac actin hypertrophic cardiomyopathy-causing mutation, over a range of increasingly complex in silico, in vitro, and in vivo Drosophila muscle models, we propose that subtle A-triad-tropomyosin perturbation can destabilize thin filament regulation, which leads to hypercontractility and triggers disease. Our efforts increase understanding of basic thin filament biology and help unravel the mechanistic basis of a complex cardiac disorder.
AB - Striated muscle contraction is regulated by the movement of tropomyosin over the thin filament surface, which blocks or exposes myosin binding sites on actin. Findings suggest that electrostatic contacts, particularly those between K326, K328, and R147 on actin and tropomyosin, establish an energetically favorable F-actin-tropomyosin configuration, with tropomyosin positioned in a location that impedes actomyosin associations and promotes relaxation. Here, we provide data that directly support a vital role for these actin residues, termed the A-triad, in tropomyosin positioning in intact functioning muscle. By examining the effects of an A295S α-cardiac actin hypertrophic cardiomyopathy-causing mutation, over a range of increasingly complex in silico, in vitro, and in vivo Drosophila muscle models, we propose that subtle A-triad-tropomyosin perturbation can destabilize thin filament regulation, which leads to hypercontractility and triggers disease. Our efforts increase understanding of basic thin filament biology and help unravel the mechanistic basis of a complex cardiac disorder.
KW - Drosophila
KW - cardiomyopathy
KW - computational modeling
KW - diastolic dysfunction
KW - hypertrophic cardiomyopathy
KW - indirect flight muscle
KW - muscle regulation
KW - sarcomere
KW - thin filament
KW - tropomyosin
KW - troponin
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U2 - 10.1016/j.celrep.2017.08.070
DO - 10.1016/j.celrep.2017.08.070
M3 - Article
C2 - 28903042
AN - SCOPUS:85029386604
SN - 2211-1247
VL - 20
SP - 2612
EP - 2625
JO - Cell Reports
JF - Cell Reports
IS - 11
ER -