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淋巴细胞在血管内皮表面的黏附和迁移是炎症反应病理过程中的重要步骤和关键环节,这一过程是由淋巴细胞表面的一类特殊黏附分子——整合素所介导的。研究显示,整合素α4β7的异常表达和活化与一些人类自身免疫疾病密切相关,如溃疡性结肠炎、克罗恩病等。整合素α4β7的生物学功能是依靠对其配体亲和性及其相关信号转导的动态调控来实现的。这种精确的动态调控机制一直以来都是整合素研究领域的热点。我们的研究发现整合素α4β7的特异性决定环(specific determining loop,SDL)与协同金属离子结合位点(the synergistic metal ion binding site,SyMBS)通过一对特殊的阳离子-π相互作用相连接。该阳离子-π相互作用的丧失严重影响了高亲和性α4β7介导的细胞稳定黏附,但是对低亲和性α4β7介导的细胞滚动黏附影响很小。破坏该阳离子-π相互作用诱导了整合素胞外区的部分伸展和胞内亚基一定程度的分离,并影响了整合素所介导的双向跨膜信号传递,表现为胞内paxillin蛋白水平上调以及paxillin与α4β7的结合增强,同时胞内FAK蛋白表达以及磷酸化水平上调。研究还发现阳离子-π相互作用的丧失抑制了整合素介导的细胞迁移。该研究首次发现阳离子-π相互作用对整合素配体结合亲和性以及信号转导的调控机制,不仅有助于我们进一步了解整合素相关的生理病理过程,而且为相关自身免疫疾病的治疗提供了一个新的药物靶点。
The adhesion and migration of lymphocytes on the vascular endothelial surface are important steps and key steps in the pathological process of inflammatory response, which is mediated by a special type of adhesion molecule on the surface of lymphocytes, integrin. Studies have shown that the abnormal expression and activation of integrin α4β7 is closely related to some autoimmune diseases in humans, such as ulcerative colitis and Crohn’s disease. The biological function of integrin α4β7 is based on the dynamic regulation of its ligand affinity and its related signal transduction. This precise dynamic regulation mechanism has long been a hot spot in integrin research. Our study found that the specific determining loop (integrin α4β7) is linked to the synergistic metal ion binding site (SyMBS) via a pair of specific cation-π interactions. The loss of this cation-π interaction severely affected the high-affinity α4β7-mediated cell adhesion, but had little effect on low-affinity α4β7-mediated cell rolling adhesion. Disruption of this cation-π interaction induces partial extension of the extracellular domain of integrin and a certain degree of separation of the intracellular subunits and affects integrin-mediated bidirectional transmembrane signaling as manifested by an upregulation of intracellular paxillin protein As well as the increased binding of paxillin to α4β7, as well as the up-regulation of intracellular FAK protein expression and phosphorylation. The study also found that the loss of the cation-π interaction inhibits integrin-mediated cell migration. This study, for the first time, found that the mechanism of cation-π interaction on integrin ligand binding affinity and signal transduction not only helps us to understand more about integrin-related physiological and pathological processes, but also to provide treatment for related autoimmune diseases A new drug target.