Localization of the binding site on intercellular adhesion molecule-3 (ICAM-3) for lymphocyte function-associated antigen 1 (LFA-1)
Localization of the binding site on intercellular adhesion molecule-3 (ICAM-3) for lymphocyte function-associated antigen 1 (LFA-1)
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DOI：
10.1074/jbc.271.39.23920
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发表时间：
1996-09-27
影响因子：
4.8
通讯作者：
Springer, TA
中科院分区：
文献类型：
--
作者：
Klickstein, LB;York, MR;Springer, TA
细胞间黏附分子3细胞间粘附分子（ICAM-3; CD 50）是静息T细胞和单核细胞上白细胞整联蛋白、淋巴细胞功能相关抗原1（LFA-1; CD 11 a/CD 18），并可能在T细胞依赖性免疫应答的初始阶段发挥重要作用，ICAM-3的单个免疫球蛋白超家族（IgSF）结构域和ICAM-3 IgSF结构域与CD 21嵌合体的缺失显示ICAM-3中存在单个LFA-1结合位点。IgSF结构域1是LFA-1结合所必需和充分的。用17种抗ICAM-3单克隆抗体进行的表位作图和功能研究表明，只有一些单克隆抗体，其表位完全在ICAM-3的结构域1内，能够阻断携带ICAM-3的细胞与纯化的LFA-1的结合，这与从结构域缺失突变体和CD 21嵌合体获得的数据一致。对ICAM-3结构域1的一组45个点突变体的分析鉴定了可能作为结合位点的一部分接触LFA-1的5个残基，Asn（23）、Ser（25）、Glu（37）、Phe（54）和Gln（75）。基于血管细胞粘附分子1（VCAM-1）的结构，通过分子建模预测这5个残基聚集在BED表面（Asn（23）和Ser（25））和C链或CD环（E37）、E链（F54）和FG环（Q75）上ICAM-3结构域1上的两个不同位置。残基Asn（23）和Ser（25）包含共有N-连接的糖基化位点。
Intercellular adhesion molecule 3 (ICAM-3; CD50) is the predominant counter receptor on resting T cells and monocytes for the leukocyte integrin, lymphocyte function associated antigen 1 (LFA-1; CD11a/CD18), and may play an important role in the initial stages of the T cell-dependent immune response, Deletion of individual immunoglobulin superfamily (IgSF) domains of ICAM-3 and ICAM-3 IgSF domain chimeras with CD21 showed there is a single LFA-1 binding site in ICAM-3 and that IgSF domain 1 is necessary and sufficient for LFA-1 binding. Epitope mapping and functional studies performed with 17 anti-ICAM-3 monoclonal antibodies demonstrated that only some monoclonal antibodies, with epitopes wholly within domain 1 of ICAM-3, were able to block binding of ICAM-3 bearing cells to purified LFA-1, in agreement with the data obtained from the domain deletion mutants and CD21 chimeras. Analysis of a panel of 45 point mutants of domain 1 of ICAM-3 identified five residues that may contact LFA-1 as part of the binding site, Asn(23), Ser(25), Glu(37), Phe(54), and Gln(75). These five residues are predicted by molecular modeling, based on the structure of vascular cell adhesion molecule 1 (VCAM-1), to cluster in two distinct locations on domain 1 of ICAM-3 on the BED face (Asn(23) and Ser(25)) and on the C strand or CD loop (E37), the E strand (F54), and the FG loop (Q75). The residues, Asn(23) and Ser(25), comprise a consensus N-linked glycosylation site.