Mayans O, van der Ven P F, Wilm M, Mues A, Young P, Fürst D O, Wilmanns M, Gautel M
European Molecular Biology Laboratory, Hamburg Outstation, Germany.
Nature. 1998 Oct 29;395(6705):863-9. doi: 10.1038/27603.
The giant muscle protein titin (connectin) is essential in the temporal and spatial control of the assembly of the highly ordered sarcomeres (contractile units) of striated muscle. Here we present the crystal structure of titin's only catalytic domain, an autoregulated serine kinase (titin kinase). The structure shows how the active site is inhibited by a tyrosine of the kinase domain. We describe a dual mechanism of activation of titin kinase that consists of phosphorylation of this tyrosine and binding of calcium/calmodulin to the regulatory tail. The serine kinase domain of titin is the first known non-arginine-aspartate kinase to be activated by phosphorylation. The phosphorylated tyrosine is not located in the activation segment, as in other kinases, but in the P + 1 loop, indicating that this tyrosine is a binding partner of the titin kinase substrate. Titin kinase phosphorylates the muscle protein telethonin in early differentiating myocytes, indicating that this kinase may act in myofibrillogenesis.
巨大的肌肉蛋白肌联蛋白（连接蛋白）对于横纹肌高度有序的肌节（收缩单位）组装的时空控制至关重要。在此，我们展示了肌联蛋白唯一催化结构域——一种自调节丝氨酸激酶（肌联蛋白激酶）的晶体结构。该结构显示了激酶结构域的一个酪氨酸如何抑制活性位点。我们描述了肌联蛋白激酶激活的双重机制，其包括该酪氨酸的磷酸化以及钙/钙调蛋白与调节尾部的结合。肌联蛋白的丝氨酸激酶结构域是首个已知通过磷酸化被激活的非精氨酸 - 天冬氨酸激酶。与其他激酶不同，磷酸化的酪氨酸并不位于激活环，而是位于P + 1环，这表明该酪氨酸是肌联蛋白激酶底物的结合伴侣。肌联蛋白激酶在早期分化的肌细胞中使肌肉蛋白隐钙蛋白磷酸化，表明该激酶可能在肌原纤维形成过程中发挥作用。
