Abstract:
Integrins are heterodimeric membrane-spanning adhesion receptors that are essential for a wide range of biological functions. Control of integrin conformational states is required for bidirectional signalling across the membrane. Key components of this control mechanism are the transmembrane and cytoplasmic domains of the alpha and beta subunits. These domains are believed to interact, holding the integrin in the inactive state, while inside-out integrin activation is accompanied by domain separation. Although there are strong indications for domain interactions, the majority of evidence is insufficient to precisely define the interaction interface. The current best model of the complex, derived from computational calculations with experimental restraints, suggests that integrin activation by the cytoplasmic protein talin is accomplished by steric disruption of the alpha/beta interface. Better atomic-level resolution structures of the alpha/beta transmembrane/cytoplasmic domain complex are still required for the resting state integrin to corroborate this. Integrin activation is also controlled by competitive interactions involving the cytoplasmic domains, particularly the beta-tails. The concept of the beta integrin tail as a focal adhesion interaction \'hub\' for interactions and regulation is discussed. Current efforts to define the structure and affinity of the various complexes formed by integrin tails, and how these interactions are controlled, e.g. by phosphorylation and localization, are described.
摘要:
整合素是异源二聚体跨膜粘附受体,对广泛的生物学功能至关重要。整联蛋白构象状态的控制对于跨膜的双向信号传导是必需的。这种控制机制的关键成分是α和β亚基的跨膜和细胞质结构域。这些领域被认为是相互作用的,将整合素保持在非活动状态,而由内而外的整合素激活则伴随着结构域的分离。尽管领域相互作用有很强的迹象,大多数证据不足以精确定义交互界面。目前最好的综合体模型,从具有实验约束的计算计算中得出,表明,整联蛋白的激活是通过α/β界面的空间破坏完成的。静息状态整联蛋白仍需要α/β跨膜/细胞质结构域复合物的更好的原子级分辨率结构来证实这一点。整合素的激活也受到涉及细胞质结构域的竞争性相互作用的控制。尤其是贝塔尾巴。讨论了β整合素尾作为局灶性粘附相互作用“枢纽”的概念,用于相互作用和调节。目前正在努力定义由整合素尾巴形成的各种复合物的结构和亲和力,以及如何控制这些相互作用,例如通过磷酸化和定位,被描述。