Structural basis for the interaction between focal adhesion kinase and CD4
Structural basis for the interaction between focal adhesion kinase and CD4
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DOI：
10.1016/j.jmb.2007.11.040
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发表时间：
2008-02-01
影响因子：
5.6
通讯作者：
Arold, Stefan T.
中科院分区：
文献类型：
--
作者：
Garron, Marie-Line;Arthos, James;Arold, Stefan T.
粘着斑激酶（FAK）和CD 4在细胞信号转导中发挥重要作用：FAK是整合素信号传导的中心组分，而CD 4在免疫防御中起重要作用。在T淋巴细胞中，FAK和CD 4定位于相同的信号复合物刺激后，无论是人类免疫缺陷病毒（HIV）gp 120糖蛋白或抗原，表明FAK和CD 4在这些细胞中的协同作用。使用晶体学和微量热法，我们在这里表明，粘着斑靶向（FAT）结构域的FAK结合特异性的CD 4内吞基序在体外。该FAT-CD 4复合物在结构和药理学上类似于具有桩蛋白LD基序的FAT形式。FAT上的CD 4结合位点呈现与HIV-1 Nef蛋白上建立的CD 4结合位点相同的特征。FAT与CD 4的结合与Lck与CD 4的结合不相容。我们进一步表明，HIV-1 gp 120触发协会的CD 4与FAK在T细胞中，在已知的条件下，解离LCK从CD 4。我们的研究结果表明，FAK-CD 4复合物是一种引发T细胞特异性信号的替代途径，它将gp 120参与与HIV感染期间独特的T细胞信号传导联系起来。在感染的细胞中，HIV-1 Net可以取代CD 4中的FAK，以保护细胞免于凋亡。(C)2007爱思唯尔有限公司保留所有权利。
Focal adhesion kinase (FAK) and CD4 fulfil vital functions in cellular signal transduction: FAK is a central component in integrin signalling, whereas CD4 plays essential roles in the immune defence. In T lymphocytes, FAK and CD4 localise to the same signalling complexes after stimulation by either the human immunodeficiency virus (HIV) gp120 glycoprotein or an antigen, suggesting the concerted action of FAK and CD4 in these cells. Using crystallography and microcalorimetry, we here show that the focal adhesion targeting (FAT) domain of FAK binds specifically to the CD4 endocytosis motif in vitro. This FAT-CD4 complex is structurally and thermodynamically similar to the one FAT forms with paxillin LD motifs. The CD4 binding site on FAT presents the same features as the established CD4 binding site on the HIV-1 Nef protein. The binding of FAT to CD4 is incompatible with the binding of Lck to CD4. We further show that HIV-1 gp120 triggers the association of CD4 with FAK in T cells, under conditions that are known to dissociate Lck from CD4. Our results suggest that the FAK-CD4 complex represents an alternative route for eliciting T-cell-specific signals and that it links gp120 engagement to distinctive T-cell signalling during HIV infection. In infected cells, HIV-1 Net may displace FAK from CD4 to protect the cells from apoptosis. (C) 2007 Elsevier Ltd. All rights reserved.