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首页> 外文期刊>Current Biology: CB >The Mechanism of Kindlin-Mediated Activation of Integrin alpha IIb beta 3
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The Mechanism of Kindlin-Mediated Activation of Integrin alpha IIb beta 3

机译：Kindlin介导的整合素αIIb beta 3激活的机制。

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Increased ligand binding to cellular integrins ("activation") plays important roles in processes such as development, cell migration, extracellular matrix assembly, tumor metastasis, hemostasis, and thrombosis [1-5]. Integrin activation encompasses both increased integrin monomer affinity and increased receptor clustering [6] and depends on integrin-talin interactions [5]. Loss of kindlins results in reduced activation of integrins [7-13]. Kindlins might promote talin binding to integrins through a cooperative mechanism [5, 14-16]; however, kindlins do not increase talin association with integrins [17]. Here, we report that, unlike talin head domain (THD), kindlin-3 has little effect on the affinity of purified monomeric alpha IIb beta 3, and it does not enhance activation by THD. Furthermore, studies with ligands of varying valency show that kindlins primarily increase cellular alpha IIb beta 3 avidity rather than monomer affinity. In platelets or nucleated cells, loss of kindlins markedly reduces alpha IIb beta 3 binding to multivalent but not monovalent ligands. Finally, silencing of kindlins reduces the clustering of ligand-occupied alpha IIb beta 3 as revealed by total internal reflection fluorescence and electron microscopy. Thus, in contrast to talins, kindlins have little primary effect on integrin alpha IIb beta 3 affinity for monovalent ligands and increase multivalent ligand binding by promoting the clustering of talin-activated integrins.
机译：配体与细胞整联蛋白结合的增加（“激活”）在诸如发育，细胞迁移，细胞外基质组装，肿瘤转移，止血和血栓形成等过程中起重要作用[1-5]。整联蛋白活化既包括增加的整联蛋白单体亲和力，也包括增加的受体簇[6]，并取决于整联蛋白-塔林相互作用[5]。损失kindlins会降低整合素的激活[7-13]。 Kindlins可能通过合作机制促进塔林素与整联蛋白的结合[5，14-16];但是，kindlins不会增加talin与整联蛋白的结合[17]。在这里，我们报告，与塔林头域（THD）不同，kindlin-3对纯化的单体αIIb beta 3的亲和力影响很小，并且不会增强THD的激活作用。此外，使用化合价不同的配体进行的研究表明，kindlins主要增加细胞αIIb beta 3的亲和力，而不是单体亲和力。在血小板或有核细胞中，kindlins的丢失显着降低了αIIb beta 3与多价而不是单价配体的结合。最终，如通过全内反射荧光和电子显微镜观察到的，kindlins的沉默降低了配体占据的αIIb beta 3的聚集。因此，与塔林蛋白相反，kindlins对整联蛋白αIIb beta 3对单价配体的亲和力几乎没有主要作用，并且通过促进塔林激活的整联蛋白的聚集而增加了多价配体的结合。

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