Interdomain tilt angle determines integrin-dependent function of the ninth and tenth FIII domains of human fibronectin.
Interdomain tilt angle determines integrin-dependent function of the ninth and tenth FIII domains of human fibronectin.
复制标题
域间倾斜角度决定了人纤连蛋白的第九和第十FIII结构域的整联蛋白依赖性功能。
DOI：
10.1074/jbc.m406976200
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发表时间：
2004-12-31
影响因子：
4.8
通讯作者：
Mardon, HJ
中科院分区：
文献类型：
--
作者：
Altroff, H;Schlinkert, R;van der Walle, CF;Bernini, A;Campbell, ID;Werner, JM;Mardon, HJ
整合素是介导多种细胞过程的信号受体的重要家族。已知丰富的细胞外基质配体纤连蛋白与整合素α5β1和αvβ3的结合依赖于纤连蛋白第十个FIII结构域上的Arg-Gly-Asp（RGD）基序。相邻的第九个FIII结构域对RGD介导的整合素α5β1结合和下游功能提供协同作用。这种协同作用的精确分子基础仍然难以捉摸。在这里，我们已经解剖进一步的功能，FIII 9整合素结合分析的FIII 9 -10域间接口的变体的生物活性，并通过确定其在溶液中的结构和动力学特性。我们证明，FIII 9对α5β1和αvβ3结合和下游功能的贡献关键取决于FIII 9和FIII 10结构域之间的结构域间倾斜。我们的数据表明，整联蛋白结合FIII 9的调制可能部分来自其空间特性，决定了RGD基序的可访问性。这些发现对整合素-配体结合的生理机制具有更广泛的意义。
Integrins are an important family of signaling receptors that mediate diverse cellular processes. The binding of the abundant extracellular matrix ligand fibronectin to integrins α5β1 and αvβ3 is known to depend upon the Arg-Gly-Asp (RGD) motif on the tenth fibronectin FIII domain. The adjacent ninth FIII domain provides a synergistic effect on RGD-mediated integrin α5β1 binding and downstream function. The precise molecular basis of this synergy remains elusive. Here we have dissected further the function of FIII9 in integrin binding by analyzing the biological activity of the FIII9–10 interdomain interface variants and by determining their structural and dynamic properties in solution. We demonstrate that the contribution of FIII9 to both α5β1 and αvβ3 binding and downstream function critically depends upon the interdomain tilt between the FIII9 and FIII10 domains. Our data suggest that modulation of integrin binding by FIII9 may arise in part from its steric properties that determine accessibility of the RGD motif. These findings have wider implications for mechanisms of integrin-ligand binding in the physiological context.