Abnormal actin binding of aberrant beta-tropomyosins is a molecular cause of muscle weakness in TPM2-related nemaline and cap myopathy

作者：Marttila Minttu; Lemola Elina; Wallefeld William; Memo Massimiliano; Donner Kati; Laing Nigel G; Marston Steven; Gronholm Mikaela; Wallgren Pettersson Carina^*

来源：Biochemical Journal, 2012, 442(1): 231-239.

DOI：10.1042/BJ20111030

• actin binding
• calcium-sensitivity
• cap myopathy
• circular dichroism (CD)
• nemaline myopathy (NM)
• beta-tropomyosin (beta-Tm)

NM (nemaline myopathy) is a rare genetic muscle disorder defined on the basis of muscle weakness and the presence of structural abnormalities in the muscle fibres, i.e. nemaline bodies. The related disorder cap myopathy is defined by cap-like structures located peripherally in the muscle fibres. Both disorders may be caused by mutations in the TPM2 gene encoding beta-Tm (tropomyosin). Tm controls muscle contraction by inhibiting actin-myosin interaction in a calcium-sensitive manner. In the present study, we have investigated the pathogenetic mechanisms underlying five disease-causing mutations in Tm. We show that four of the mutations cause changes in affinity for actin, which may cause muscle weakness in these patients, whereas two show defective Ca2+ activation of contractility. We have also mapped the amino acids altered by the mutation to regions important for actin binding and note that two of the mutations cause altered protein conformation, which could account for impaired actin affinity.

• 出版日期2012-2-15
• 单位河北医科大学