Structures of T Cell immunoglobulin mucin receptors 1 and 2 reveal mechanisms for regulation of immune responses by the TIM receptor family.
Structures of T Cell immunoglobulin mucin receptors 1 and 2 reveal mechanisms for regulation of immune responses by the TIM receptor family.
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DOI：
10.1016/j.immuni.2007.01.014
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发表时间：
2007-03
期刊：
影响因子：
32.4
通讯作者：
Casasnovas JM
中科院分区：
文献类型：
--
作者：
Santiago C;Ballesteros A;Tami C;Martínez-Muñoz L;Kaplan GG;Casasnovas JM
T细胞免疫球蛋白粘蛋白（TIM）受体参与免疫应答、自身免疫和变态反应的调节。小鼠mTIM-1和mTIM-2受体的N-末端配体结合结构域的结构揭示了免疫球蛋白（IG）折叠，其中4个Cys残基将独特的CC '环桥接到GFC β折叠。该结构在TIM家族中表现出两种配体识别模式。mTIM-1结构鉴定了嗜同性TIM-TIM粘附相互作用，而mTIM-2结构域形成防止嗜同性结合的二聚体。生化，突变和细胞粘附分析证实了不同的配体结合模式所揭示的结构。mTIM-1的结构特征在人TIM-1中似乎是保守的，其也介导嗜同性相互作用。胞外粘蛋白结构域通过IG结构域增强结合，调节TIM受体功能。这些结果解释了小鼠受体的不同免疫功能以及TIM-1作为细胞粘附受体在肾再生和癌症中的作用。
The T cell immunoglobulin mucin (TIM) receptors are involved in the regulation of immune responses, autoimmunity, and allergy. Structures of the N-terminal ligand binding domain of the murine mTIM-1 and mTIM-2 receptors revealed an immunoglobulin (Ig) fold, with four Cys residues bridging a distinctive CC′ loop to the GFC β-sheet. The structures showed two ligand-recognition modes in the TIM family. The mTIM-1 structure identified a homophilic TIM-TIM adhesion interaction, whereas the mTIM-2 domain formed a dimer that prevented homophilic binding. Biochemical, mutational, and cell adhesion analyses confirmed the divergent ligand-binding modes revealed by the structures. Structural features characteristic of mTIM-1 appear conserved in human TIM-1, which also mediated homophilic interactions. The extracellular mucin domain enhanced binding through the Ig domain, modulating TIM receptor functions. These results explain the divergent immune functions described for the murine receptors and the role of TIM-1 as a cell adhesion receptor in renal regeneration and cancer.
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