Changing ligand specificities of alpha v beta 1 and alpha v beta 3 integrins by swapping a short diverse sequence of the beta subunit
Changing ligand specificities of alpha v beta 1 and alpha v beta 3 integrins by swapping a short diverse sequence of the beta subunit
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DOI：
10.1074/jbc.272.32.19794
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发表时间：
1997-08-08
影响因子：
4.8
通讯作者：
Takada, Y
中科院分区：
文献类型：
--
作者：
Takagi, J;Kamata, T;Takada, Y
整合素通过与多种细胞或细胞外基质配体相互作用介导信号转导。整合素α v β 3识别纤维蛋白原、血管性血友病因子和玻连蛋白，而α v β 1不识别。我们通过交换β 1和β 3亚基的I结构域样结构中高度多样的序列，研究了定义这些整合素配体特异性的机制。当β 1的序列CTSEQNC（残基187-193）被β 3的相应CYD-MKTTC序列取代时，α v β 1的配体特异性发生改变。突变体（α v β 1-3-1）与α v β 3一样，识别纤维蛋白原、血管性血友病因子和玻连蛋白（功能获得效应）。α v β 1-3-1突变体被募集到纤维蛋白原和玻连蛋白上的焦点接触，表明突变体在粘附上转导细胞内信号。相互β 3-1-3突变阻断α v β 3与这些多配体和LM 609（一种功能阻断抗α v β 3抗体）的结合。这些结果表明，高度发散的序列是整合素配体特异性的关键决定因素。此外，数据支持最近的假设模型的I域的β，其中该序列位于配体结合位点。
Integrins mediate signal transduction through interaction with multiple cellular or extracellular matrix ligands. Integrin alpha v beta 3 recognizes fibrinogen, von Willebrand factor, and vitronectin, while alpha v beta 1 does not. We studied the mechanisms for defining ligand specificity of these integrins by swapping the highly diverse sequences in the I domain-like structure of the beta 1 and beta 3 subunits. When the sequence CTSEQNC (residues 187-193) of beta 1 is replaced with the corresponding CYD-MKTTC sequence of beta 3, the ligand specificity of alpha v beta 1 is altered. The mutant (alpha v beta 1-3-1), like alpha v beta 3, recognizes fibrinogen, von Willebrand factor, and vitronectin (a gain-of-function effect). The alpha v beta 1-3-1 mutant is recruited to focal contacts on fibrinogen and vitronectin, suggesting that the mutant transduces intracellular signals on adhesion. The reciprocal beta 3-1-3 mutation blocks binding of alpha v beta 3 to these multiple ligands and to LM609, a function-blocking anti-alpha v beta 3 antibody. These results suggest that the highly divergent sequence is a key determinant of integrin ligand specificity. Also, the data support a recent hypothetical model of the I domain of beta, in which the sequence is located in the ligand binding site.