阳离子-π相互作用对整合素α_4β_7配体结合亲和性及其信号转导的调控  

Cation-π Interaction Regulates Ligand Binding Affinity and Signaling of Integrin α_4β_7

作　　者：潘有东[1] 张坤[1] 岳姣[1] 陈剑峰[1] 

机构地区：[1]细胞生物学国家重点实验室(筹)中国科学院上海生命科学研究院生物化学与细胞生物学研究所,上海200031

出　　处：《中国基础科学》2011年第3期33-37,共5页China Basic Science

摘　　要：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。Integrin α4β7 is an important lymphocyte homing receptor which can mediate both rolling and firm adhesion of lymphocytes and plays a vital role in lymphocyte migration and tissue-specific homing.Aberrant expression and activation of integrin α4β7 have been implicated in the development of human inflammatory diseases,such as Crohn＇s disease and ulcerative colitis.The ligand binding affinity and signaling of integrin are regulated dynamically and precisely by different stimuli,and are associated with the conformational rearrangement of the integrin molecule.We found that Phe185（F185）,a highly conserved aromatic residue in β7-subunit,links the specificity-determining loop（SDL） and the synergistic metal ion binding site（SyMBS） through cation-π interaction.Mutations of F185 that disrupted the SyMBS cation-F185 interaction led to deficient firm cell adhesion mediated by high affinity α4β7;but slightly affected rolling adhesion mediated by low affinity α4β7.Abolishment of SyMBS cation-F185 interaction induced partial extension of integrin ectodomain and separation of cytoplasmic tails,and disrupted α4β7 mediated bidirectional signaling.Furthermore,loss of SyMBS cation-F185 interaction promoted paxillin-integrin binding and FAK phosphorylation with up-regulation of paxillin and FAK expression.In addition,integrin α4β7-mediated cell migration was decreased by the abolishment of SyMBS cation-F185 interaction.Thus,these findings reveal a cation-π interaction playing vital roles in the regulation of integrin affinity,signaling and biological functions,which will facilitate the development of new therapeutics for integrin-related diseases.

关 键 词：整合素 阳离子-π 相互作用 细胞黏附 细胞迁移 信号转导 

分 类 号：Q26[生物学—细胞生物学]