Evidence that monoclonal antibodies directed against the integrin β subunit plexin/semaphorin/integrin domain stimulate function by inducing receptor extension
Evidence that monoclonal antibodies directed against the integrin β subunit plexin/semaphorin/integrin domain stimulate function by inducing receptor extension
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DOI：
10.1074/jbc.m412240200
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发表时间：
2005-02-11
影响因子：
4.8
通讯作者：
Humphries, MJ
中科院分区：
文献类型：
--
作者：
Mould, AP;Travis, MA;Humphries, MJ
整联蛋白的整体结构是连接到两条长腿的配体结合头。腿可以在“膝盖”处表现出明显的弯曲，并且已经提出，当整联蛋白从低亲和力状态转变为高亲和力状态时，腿经历显著的拉直。膝盖区域包含来自α和β亚基的结构域，包括β亚基的N末端丛蛋白/信号蛋白/整联蛋白（PSI）结构域。膝结构域在整合素配体结合的调节中所起的作用尚不确定。在这里，我们表明：（i）单克隆抗体（mAb）N29和SE 3在β（1）亚基PSI结构域中具有表位，并刺激配体与α（5）β（1）结合;（ii）N29和SE 3引起改变头部区域的配体结合活性的长程构象变化;（iii）这些mAb的刺激作用依赖于形成α亚基膝的一部分的calf-1结构域;和（iv）8 E3和N29的表位定位在PSI的N末端附近，并且可能位于该结构域面向α亚基的一侧。综上所述，我们的数据表明，这些单克隆抗体的结合导致PSI和calf-1结构域的勒韦林分离，从而导致α和β亚基膝盖分离。从我们的发现中可以得出几个主要的推论。首先，PSI结构域似乎形成与α亚基的界面的一部分，该α亚基通常将整联蛋白限制在弯曲状态。第二，PSI结构域对于从膝盖到头部的构象变化的转导是重要的。第三，伸直可能提供控制整合素-配体识别的一般机制。
The overall structure of integrins is that of a ligand-binding head connected to two long legs. The legs can exhibit a pronounced bend at the "knees," and it has been proposed that the legs undergo a dramatic straightening when integrins transit from a low affinity to a high affinity state. The knee region contains domains from both a and beta subunits, including the N-terminal plexin/semaphorin/integrin (PSI) domain of the beta subunit. The role played by the knee domains in the regulation of integrinligand binding is uncertain. Here we show that: (i) monoclonal antibodies (mAbs) N29 and SE3 have epitopes in the beta(1) subunit PSI domain and stimulate ligand binding to alpha(5)beta(1); (ii) N29 and SE3 cause long range conformational changes that alter the ligand binding activity of the head region; (iii) the stimulatory action of these mAbs is dependent on the calf-1 domain, which forms part of the a subunit knee; and (iv) the epitopes of 8E3 and N29 map close to the extreme N terminus of the PSI and are likely to lie on the side of this domain that faces the a subunit. Taken together, our data suggest that the binding of these mAbs results in a levering apart of the PSI and calf-1 domains, and thereby causes the a and beta subunit knees to separate. Several major inferences can be drawn from our findings. First, the PSI domain appears to form part of an interface with the a subunit that normally restrains the integrin in a bent state. Second, the PSI domain is important for the transduction of conformational changes from the knee to head. Third, unbending is likely to provide a general mechanism for control of integrin-ligand recognition.