Functional effects of congenital myopathy-related mutations in gamma-tropomyosin gene
详细信息 查看全文
- 作者：Katarzyna Robaszkiewicz ; El?bieta Dudek ; Andrzej A. Kasprzak ; Joanna Moraczewska
- 关键词：¦ÃTM ; isoform of tropomyosin from slow type 1 muscle fibers ; skTM ; recombinant skeletal ¦Á tropomyosin ; TPM3 ; human ¦Ã-tropomyosin gene ; Tn ; troponin complex ; NM ; nemaline myopathy ; CD ; cap disease ; CFTD ; congenital fiber type disproportion ; S1 ; myosin su
- 刊名：Biochimica et Biophysica Acta (BBA)/Molecular Basis of Disease
- 出版年：2012
- 出版时间：October, 2012
- 年：2012
- 卷：1822
- 期：10
- 页码：1562-1569
- 全文大小：812 K
文摘
Missense mutations in human TPM3 gene encoding ¦Ã-tropomyosin expressed in slow muscle type 1 fibers, were associated with three types of congenital myopathies¡ªnemaline myopathy, cap disease and congenital fiber type disproportion. Functional effects of the following substitutions: Leu100Met, Ala156Thr, Arg168His, Arg168Cys, Arg168Gly, Lys169Glu, and Arg245Gly, were examined in biochemical assays using recombinant tropomyosin mutants and native proteins isolated from skeletal muscle. Most, but not all, mutations decreased the affinity of tropomyosin for actin alone and in complex with troponin (¡À Ca2 +). All studied tropomyosin mutants reduced Ca-induced activation but had no effect on the inhibition of actomyosin cross-bridges. Ca2 +-sensitivity of the actomyosin interactions, as well as cooperativity of myosin-induced activation of the thin filament was affected by individual tropomyosin mutants with various degrees. Decreased motility of the reconstructed thin filaments was a result of combined functional defects caused by myopathy-related tropomyosin mutants. We conclude that muscle weakness and structural abnormalities observed in TPM3-related congenital myopathies result from reduced capability of the thin filament to fully activate actin-myosin cross-bridges.