TY - JOUR

T1 - The effect of the Arg91Gly and Glu139del mutations in β-tropomyosin associated with congenital myopathy of human skeletal muscles on actin–myosin interaction

AU - Rysev, N.A.

AU - Karpicheva, O.E.

AU - Sirenko, V. V.

AU - Simonyan, A. O.

AU - Redwood, Charles S.

AU - Borovikov, Y.S.

N1 - Rysev, N.A., Karpicheva, O.E., Sirenko, V.V. et al. The Effect of the Arg91Gly and Glu139del Mutations in β-Tropomyosin Associated with Congenital Myopathy of Human Skeletal Muscles on Actin–Myosin Interaction. Cell Tiss. Biol. 12, 238–246 (2018). https://doi.org/10.1134/S1990519X18030112

PY - 2018

Y1 - 2018

N2 - The structural changes in proteins of the contractile apparatus of muscle fiber and the violation of their function due to point mutations in these proteins can be a cause of many hereditary diseases of human muscular tissue. Some such diseases are cap-myopathy and distal arthrogryposis, which may be connected with tropomyosin mutations. The deletion of glutamic-acid residue at position 139 of β-tropomyosin leads to the development of cap-myopathy, and the replacement of arginine at position 91 with glycine in this protein is linked to distal arthrogryposis. To understand how the Arg91Gly and Glu139del mutations disrupt the coordinated work of the contractile system of muscle fibers, recombinant wild-type and mutant β-tropomyosins were overexpressed and incorporated into thin filaments of ghost-muscle fiber. Fluorescent probes of 1,5-IAEDANS or FITC-phalloidin were specifically linked to the Cys707 of the myosin subfragment-1 and the three neighboring actin monomers, respectively. The polarized-microfluorimetry technique was used to study the spatial arrangements of actin and myosin in mimicking different stages of the ATPase cycle (in the presence of ADP or ATP and in the absence of a nucleotide) at low and high concentration of calcium ions. Both mutations were shown to change the conformational rearrangements of the myosin head and actin in the ATP hydrolysis cycle, which may be caused by abnormal behavior of the mutant tropomyosins during regulation. The altered work of the contractile system may be a cause of muscle weakness in congenital myopathies associated with these mutations.

AB - The structural changes in proteins of the contractile apparatus of muscle fiber and the violation of their function due to point mutations in these proteins can be a cause of many hereditary diseases of human muscular tissue. Some such diseases are cap-myopathy and distal arthrogryposis, which may be connected with tropomyosin mutations. The deletion of glutamic-acid residue at position 139 of β-tropomyosin leads to the development of cap-myopathy, and the replacement of arginine at position 91 with glycine in this protein is linked to distal arthrogryposis. To understand how the Arg91Gly and Glu139del mutations disrupt the coordinated work of the contractile system of muscle fibers, recombinant wild-type and mutant β-tropomyosins were overexpressed and incorporated into thin filaments of ghost-muscle fiber. Fluorescent probes of 1,5-IAEDANS or FITC-phalloidin were specifically linked to the Cys707 of the myosin subfragment-1 and the three neighboring actin monomers, respectively. The polarized-microfluorimetry technique was used to study the spatial arrangements of actin and myosin in mimicking different stages of the ATPase cycle (in the presence of ADP or ATP and in the absence of a nucleotide) at low and high concentration of calcium ions. Both mutations were shown to change the conformational rearrangements of the myosin head and actin in the ATP hydrolysis cycle, which may be caused by abnormal behavior of the mutant tropomyosins during regulation. The altered work of the contractile system may be a cause of muscle weakness in congenital myopathies associated with these mutations.

KW - actin–myosin interaction

KW - hereditary myopathy

KW - muscle fiber

KW - mutation in tropomyosin

KW - polarized fluorescence

KW - regulation of muscle contraction

UR - http://www.scopus.com/inward/record.url?scp=85048500711&partnerID=8YFLogxK

U2 - 10.1134/S1990519X18030112

DO - 10.1134/S1990519X18030112

M3 - Article

VL - 12

SP - 238

EP - 246

JO - Cell and Tissue Biology

JF - Cell and Tissue Biology

SN - 1990-519X

IS - 3

ER -