Effects of myopathy-causing mutations R91P and R245G in the TPM3 gene on structural and functional properties of slow skeletal muscle tropomyosin

• Published in: Biochemical and biophysical research communications Vol. 534; pp. 8 - 13
• Main Authors: Gonchar, Anastasiia D., Kopylova, Galina V., Kochurova, Anastasia M., Berg, Valentina Y., Shchepkin, Daniil V., Koubasova, Natalia A., Tsaturyan, Andrey K., Kleymenov, Sergey Y., Matyushenko, Alexander M., Levitsky, Dmitrii I.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01-01-2021
• Subjects: Actins - metabolism; Differential scanning calorimetry; Humans; In vitro motility Assay; Molecular dynamics; Molecular Dynamics Simulation; Muscle, Skeletal - physiopathology; Myopathic mutations; Myopathies, Structural, Congenital - genetics; Point Mutation; Protein Multimerization; Slow skeletal muscles; Tropomyosin; Tropomyosin - chemistry; Tropomyosin - genetics; Tropomyosin - metabolism; Troponin - metabolism; Viscosity; Tpm; Differential scanning calorimetry; Myopathic mutations; Slow skeletal muscles; Tropomyosin; DSC; Molecular dynamics; Tn; CFTD; In vitro motility Assay
• ISSN: 0006-291X; 1090-2104
• DOI: 10.1016/j.bbrc.2020.11.103

Tropomyosin (Tpm) is an actin-binding protein that plays a crucial role in the regulation of muscle contraction. Numerous point mutations in the TPM3 gene encoding Tpm of slow skeletal muscles (Tpm 3.12 or γ-Tpm) are associated with the genesis of various congenital myopathies. Two of these mutations, R91P and R245G, are associated with congenital fiber-type disproportion (CFTD) characterized by hypotonia and generalized muscle weakness. We applied various methods to investigate how these mutations affect the structural and functional properties of γγ-Tpm homodimers. The results show that both these mutations lead to strong structural changes in the γγ-Tpm molecule and significantly impaired its functional properties. These changes in the Tpm properties caused by R91P and R245G mutations give insight into the molecular mechanism of the CFTD development and the weakness of slow skeletal muscles observed in this inherited disease.
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•Congenital fiber-type disproportion (CFTD) is inherited disease of slow skeletal muscles.•Mutations R91P and R245G in tropomyosin (Tpm) γ-Tpm isoform lead to CFTD.•We studied properties of γγ-Tpm homodimers with these mutations in both γ-chains.•Both mutations destabilized γγ-Tpm molecule and impaired its functional properties.•The results allow one to explain how R91P and R245G mutations in γγ-Tpm can lead to CFTD.