Stimulation of sky tyrosine phosphorylation by bovine protein S - Domains involved in the receptor-ligand interaction
Stimulation of sky tyrosine phosphorylation by bovine protein S - Domains involved in the receptor-ligand interaction
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DOI：
10.1111/j.1432-1033.1997.t01-2-00147.x
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发表时间：
1997-05-15
期刊：
影响因子：
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通讯作者：
De Frutos, PG
中科院分区：
文献类型：
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作者：
Nyberg, P;He, XH;De Frutos, PG
蛋白S是一种抗凝血维生素K依赖性血浆糖蛋白，在凝血因子Va和VIIIa的降解中作为活化蛋白C的辅因子。已经提出蛋白S具有作为生长因子的额外功能。已发现蛋白S和结构相似的蛋白Gas 6刺激受体酪氨酸激酶的Axl/Sky家族的成员。Human Gas 6能够激活Axl和Sky。相比之下，牛蛋白S激活人Sky及其鼠同源物，而人蛋白S激活鼠Sky但不激活人受体。在本调查中，我们研究了这种差异的结构背景。使用具有来自人类和牛来源的结构域的蛋白S嵌合体，我们发现只有那些具有来自牛蛋白S的类固醇激素结合球蛋白样（SHBG）区域的嵌合体激活人类Sky，表明SHBG区域对于相互作用是必不可少的，这一观察结果通过C4 b结合蛋白抑制Sky磷酸化得到证实，C4 b结合蛋白是一种与蛋白S的SHBG区域紧密相互作用的血浆蛋白。另一种嵌合分子，由N-末端4-羧基谷氨酸含域（Gla域）和两个表皮生长因子样域的人因子IX，和SHBG区的牛蛋白S，刺激受体的效率较低。针对蛋白S的Gla结构域的抗体抑制牛蛋白S对人Sky的激活。这些结果表明，蛋白S的N-末端结构域不是必需的受体的激活，但有助于相互作用的亲和力。我们的数据表明，蛋白S可能是一个配体的天空在某些物种中，尽管缺乏活性的人蛋白S对人类的天空。牛/人蛋白S物种的差异将是一个有用的模型，以建立天空和它的配体之间的相互作用的结构要求。
Protein S is an anticoagulant vitamin-K-dependent plasma glycoprotein, which acts as a cofactor to activated protein C in the degradation of coagulation factors Va and VIIIa. It has been proposed that protein S has an additional function as a growth factor. Protein S and a structurally similar protein, Gas6, have been found to stimulate members of the Axl/Sky family of receptor tyrosine kinases. Human Gas6 is able to activate Axl and Sky. In contrast, while bovine protein S activates human Sky and its murine homologue, human protein S activates murine Sky but not the human receptor. In the present investigation, we studied the structural background of this species difference. Using protein S chimeras with domains from human and bovine origin, we found that only those chimeras with the steroid-hormone-binding globulin like (SHBG) region from bovine protein S activate human Sky, indicating that the SHBG region is essential for the interaction, This observation was confirmed by inhibition of Sky phosphorylation by C4b-binding protein, a plasma protein that interacts tightly with the SHBG region of protein S. Another chimeric molecule, composed of the N-terminal 4-carboxyglutamic-acid-containing domain (Gla domain) and the two epidermal-growth-factor-like domains of human factor IX, and the SHBG region of bovine protein S, stimulated the receptor less efficiently. Antibodies directed against the Gla domain of protein S, inhibited the activation of human Sky by bovine protein S. These results indicate that the N-terminal domains of protein S are not essential for activation of the receptor, but contribute to the affinity of the interaction. Our data suggest that protein S might be a ligand of Sky in some species despite the lack of activity of human protein S on human Sky. The bovine/human protein S species difference will be a useful model to establish the structural requirements for the interaction between Sky and its ligands.