The CC′ and DE Loops in Ig Domains 1 and 2 of MAdCAM-1 Play Different Roles in MAdCAM-1 Binding to Low- and High-affinity Integrin α4β7
The CC′ and DE Loops in Ig Domains 1 and 2 of MAdCAM-1 Play Different Roles in MAdCAM-1 Binding to Low- and High-affinity Integrin α4β7
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DOI：
10.1074/jbc.m110.208900
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发表时间：
2011-04-08
影响因子：
4.8
通讯作者：
Chen, JianFeng
中科院分区：
文献类型：
--
作者：
Sun, Hao;Wu, YuMei;Chen, JianFeng
淋巴细胞归巢受整联蛋白及其配体之间的动态相互作用的调节。整合素 α(4)β(7) 通过调节其与配体粘膜地址细胞粘附分子 1 (MAdCAM-1) 的亲和力来介导淋巴细胞的滚动和牢固粘附。尽管先前的研究已经揭示了 α(4)β(7)-MAdCAM-1 结合的一些机制，但人们对低亲和力和高亲和力 α(4)β(7)-MAdCAM-1 相互作用的不同分子基础知之甚少，这些相互作用分别介导淋巴细胞的滚动和牢固粘附。在这里，我们发现 MAdCAM-1 免疫球蛋白结构域 1 和 2（D1 和 D2）中的两个环在 MAdCAM-1 与低亲和力（非活性）和高亲和力（活性）α(4)β(7) 结合中发挥不同的作用。 D1 的 CC` 环中的 Asp-42 对于 MAdCAM-1 与低亲和力和高亲和力 α(4)β(7) 的结合是不可或缺的。除 Arg-39 和 Ser-44 之外的其他 CC` 环残基对于 MAdCAM-1 与 SDF-1 α 或踝蛋白激活的非活性 α(4)β(7) 和 α(4)β(7) 结合是必需的，但对于 MAdCAM-1 与 Mn2+ 激活的 α(4)β(7) 结合不是必需的。 DE 环残基的单个氨基酸取代会轻微降低 MAdCAM-1 与非活性和活性 α(4)β(7) 的结合。值得注意的是，去除 DE 环极大地削弱了 MAdCAM-1 与失活和 SDF-1 α 或 talin 激活的 α(4)β(7) 的结合，但仅降低了 MAdCAM-1 与 Mn2+ 激活的 α(4)β(7) 结合的 60%。此外，DE环残基对于稳定低亲和力α(4)β(7)-MAdCAM-1相互作用很重要。因此，我们的研究结果证明了 CC` 和 DE 环在低亲和力和高亲和力 alpha(4)beta(7) 识别 MAdCAM-1 中的不同作用，并表明由不同刺激激活的非活性 alpha(4)beta(7) 和 alpha(4)beta(7) 具有不同的构象，对 MAdCAM-1 结合具有不同的结构要求。
Lymphocyte homing is regulated by the dynamic interaction between integrins and their ligands. Integrin alpha(4)beta(7) mediates both rolling and firm adhesion of lymphocytes by modulating its affinity to the ligand, mucosal addressin cell adhesion molecule-1 (MAdCAM-1). Although previous studies have revealed some mechanisms of alpha(4)beta(7)-MAdCAM-1 binding, little is known about the different molecular bases of the low- and high-affinity alpha(4)beta(7)-MAdCAM-1 interactions, which mediate rolling and firm adhesion of lymphocytes, respectively. Here, we found that two loops in immunoglobulin domains 1 and 2 (D1 and D2) of MAdCAM-1 played different roles in MAdCAM-1 binding to low-affinity (inactive) and high-affinity (activated) alpha(4)beta(7). The Asp-42 in the CC` loop of D1 was indispensable for MAdCAM-1 binding to both low-affinity and high-affinity alpha(4)beta(7). The other CC` loop residues except for Arg-39 and Ser-44 were essential for MAdCAM-1 binding to both inactive alpha(4)beta(7) and alpha(4)beta(7) activated by SDF-1 alpha or talin, but not required for MAdCAM-1 binding to Mn2+-activated alpha(4)beta(7). Single amino acid substitution of the DE loop residues mildly decreased MAdCAM-1 binding to both inactive and activated alpha(4)beta(7). Notably, removal of the DE loop greatly impaired MAdCAM-1 binding to inactive and SDF-1 alpha- or talin-activated alpha(4)beta(7), but only decreased 60% of MAdCAM-1 binding to Mn2+-activated alpha(4)beta(7). Moreover, DE loop residues were important for stabilizing the low-affinity alpha(4)beta(7)-MAdCAM-1 interaction. Thus, our findings demonstrate the distinct roles of the CC` and DE loops in the recognition of MAdCAM-1 by low-and high-affinity alpha(4)beta(7) and suggest that the inactive alpha(4)beta(7) and alpha(4)beta(7) activated by different stimuli have distinct conformations with different structural requirements for MAdCAM-1 binding.