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首页> 外文期刊>Biochimica et biophysica acta: BBA: International journal of biochemistry, biophysics and molecular biololgy. Proteins and Proteomics >Functional effects of substitutions I92T and V95A in actin-binding period 3 of tropomyosin
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Functional effects of substitutions I92T and V95A in actin-binding period 3 of tropomyosin

机译：代置I92T和V95A在肌蛋白结合时期3的函数效应

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摘要

Tropomyosin polymerizes along actin filaments and together with troponin regulates muscle contraction in a Ca-dependent manner. Actin-binding periods are homologous residues, which repeat along tropomyosin sequence, form tropomyosin-actin interface and determine regulatory functions. To learn how period 3 is involved in tropomyosin functions we examined effects of two mutations in Tpm1.1, 192T and V95A, which have been linked to dilated and hypertrophic cardiomyopathies characterized respectively by hyper- and hypocontractile phenotypes. In this work the functional consequences of both mutations were studied in vitro by using actin thin filaments reconstituted in the presence of mutant Tpm1.1 homodimers carrying the substitutions in both tropomyosin chains, Tpm1.1 heterodimers with substitution only in one Tpm1.1 chain, and Tpm1.1/Tpm2.2 heterodimers with substitution in Tpm1.1 chain and wild type Tpm2.2 in the second chain. The presence of the substitution 192T decreased the tropomyosin affinity for actin, abolished Ca2+-dependent activation of the actomyosin ATPase, decreased the sensitivity of the tropomyosin-troponin complex to subsaturating Ca2+ concentrations and reduced the cooperativity of the myosin-induced transition of the thin filament to a fully active state. The substitution V95A had opposite effects: increased actin affinity, increased the actomyosin ATPase activity above the level observed for wild type Tpm and increased cooperativity of myosin-induced activation of the thin filaments reconstructed with homo- and heterodimers of tropomyosin. Substitutions I92T and V95A were dominant, but the formation of heterodimers modified the effects observed for homodimers.
机译：Tropomyosin沿着肌动蛋白长丝聚合，并与肌钙蛋白一起调节肌肉收缩以CA依赖性方式。肌动蛋白结合时期是同源残留物，其沿着对原鸡序列重复，形成肌醇肌蛋白界面并确定调节功能。为了了解如何参与TPM1.1,192T和V95A中的两种突变的效果，该突变与分别通过超微和下脱喉表型分别的扩张和肥厚性心肌病相关的两种突变。在这项工作中，通过使用在突变体TPM1.1同型二聚体存在下重建的肌动蛋白薄长丝来研究两种突变的功能后果.TPM1.1异二聚体仅在一个TPM1.1链中取代，和TPM1.1 / TPM2.2的异二聚体在TPM1.1链中取代和野生型TPM2.2在第二链中。替代成因192T的存在降低了肌动蛋白的对肌蛋白的亲和力，废除了Ca2 +依赖性活化的肌动酶ATP酶，降低了对肌瘤 - 肌钙蛋白复合物对子饱和Ca2 +浓度的敏感性，并降低了肌苷诱导的薄丝霉素的转变的合作性完全活跃的状态。替代V95A具有相反的影响：增加肌动蛋白亲和力，增加了野生型TPM的水平上方的肌动素ATP酶活性，并且增加了肌菌素诱导的肌肤诱导的薄细丝的激活的合作性，其与原型卵状多聚合物重建的薄长丝的活化。取代I92T和V95A是显性的，但是异二聚体的形成修饰了对同源过二聚体观察到的效果。

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