TY - JOUR

T1 - Looking for Targets to Restore the Contractile Function in Congenital Myopathy Caused by Gln147Pro Tropomyosin

AU - Karpicheva, Olga E.

AU - Simonyan, Armen O.

AU - Rysev, Nikita A.

AU - Redwood, Charles S.

AU - Borovikov, Yurii S.

N1 - Publisher Copyright: © 2020 by the authors. Licensee MDPI, Basel, Switzerland.

PY - 2020/10/2

Y1 - 2020/10/2

N2 - We have used the technique of polarized microfluorimetry to obtain new insight into the pathogenesis of skeletal muscle disease caused by the Gln147Pro substitution in β-tropomyosin (Tpm2.2). The spatial rearrangements of actin, myosin and tropomyosin in the single muscle fiber containing reconstituted thin filaments were studied during simulation of several stages of ATP hydrolysis cycle. The angular orientation of the fluorescence probes bound to tropomyosin was found to be changed by the substitution and was characteristic for a shift of tropomyosin strands closer to the inner actin domains. It was observed both in the absence and in the presence of troponin, Ca2+ and myosin heads at all simulated stages of the ATPase cycle. The mutant showed higher flexibility. Moreover, the Gln147Pro substitution disrupted the myosin-induced displacement of tropomyosin over actin. The irregular positioning of the mutant tropomyosin caused premature activation of actin monomers and a tendency to increase the number of myosin cross-bridges in a state of strong binding with actin at low Ca2+.

AB - We have used the technique of polarized microfluorimetry to obtain new insight into the pathogenesis of skeletal muscle disease caused by the Gln147Pro substitution in β-tropomyosin (Tpm2.2). The spatial rearrangements of actin, myosin and tropomyosin in the single muscle fiber containing reconstituted thin filaments were studied during simulation of several stages of ATP hydrolysis cycle. The angular orientation of the fluorescence probes bound to tropomyosin was found to be changed by the substitution and was characteristic for a shift of tropomyosin strands closer to the inner actin domains. It was observed both in the absence and in the presence of troponin, Ca2+ and myosin heads at all simulated stages of the ATPase cycle. The mutant showed higher flexibility. Moreover, the Gln147Pro substitution disrupted the myosin-induced displacement of tropomyosin over actin. The irregular positioning of the mutant tropomyosin caused premature activation of actin monomers and a tendency to increase the number of myosin cross-bridges in a state of strong binding with actin at low Ca2+.

KW - congenital myopathy

KW - disease-causing mutations

KW - tropomyosin-troponin regulation

KW - muscle contraction

KW - spatial rearrangements

KW - Congenital myopathy

KW - Tropomyosin-troponin regulation

KW - Disease-causing mutations

KW - Spatial rearrangements

KW - Muscle contraction

UR - https://www.mdpi.com/1422-0067/21/20/7590

UR - http://www.scopus.com/inward/record.url?scp=85092929200&partnerID=8YFLogxK

U2 - 10.3390/ijms21207590

DO - 10.3390/ijms21207590

M3 - Article

VL - 21

JO - International Journal of Molecular Sciences

JF - International Journal of Molecular Sciences

SN - 1422-0067

IS - 20

M1 - 7590

ER -