Department of Biological Sciences, Columbia University, New York, NY 10027, USA.
Department of Biological Sciences, Columbia University, New York, NY 10027, USA; Graduate Program in Biochemistry and Molecular Biophysics, Columbia University, New York, NY 10032, USA.
Cell. 2014 Mar 13;156(6):1235-1246. doi: 10.1016/j.cell.2014.01.056.
The giant elastic protein titin is a determinant factor in how much blood fills the left ventricle during diastole and thus in the etiology of heart disease. Titin has been identified as a target of S-glutathionylation, an end product of the nitric-oxide-signaling cascade that increases cardiac muscle elasticity. However, it is unknown how S-glutathionylation may regulate the elasticity of titin and cardiac tissue. Here, we show that mechanical unfolding of titin immunoglobulin (Ig) domains exposes buried cysteine residues, which then can be S-glutathionylated. S-glutathionylation of cryptic cysteines greatly decreases the mechanical stability of the parent Ig domain as well as its ability to fold. Both effects favor a more extensible state of titin. Furthermore, we demonstrate that S-glutathionylation of cryptic cysteines in titin mediates mechanochemical modulation of the elasticity of human cardiomyocytes. We propose that posttranslational modification of cryptic residues is a general mechanism to regulate tissue elasticity.
巨大的弹性蛋白 titin 是舒张期左心室充盈量的决定因素，也是心脏病发病机制的决定因素。Titin 已被确定为 S-谷胱甘肽化的靶点，S-谷胱甘肽化是一氧化氮信号级联的终产物，可增加心肌弹性。然而，S-谷胱甘肽化如何调节 titin 和心脏组织的弹性尚不清楚。在这里，我们表明 titin 免疫球蛋白 (Ig) 结构域的机械展开会暴露出埋藏的半胱氨酸残基，然后这些半胱氨酸残基可以被 S-谷胱甘肽化。隐蔽半胱氨酸的 S-谷胱甘肽化极大地降低了亲本 Ig 结构域的机械稳定性及其折叠能力。这两种效应都有利于 titin 更具伸展性的状态。此外，我们证明 titin 中隐蔽半胱氨酸的 S-谷胱甘肽化介导了人心肌细胞弹性的机械化学调节。我们提出，隐匿残基的翻译后修饰是调节组织弹性的一般机制。
