Tan K, Casasnovas J M, Liu J H, Briskin M J, Springer T A, Wang J H
Laboratory of Immunobiology Dana-Farber Cancer Institute 44 Binney Street, Boston, MA 02115, USA.
Structure. 1998 Jun 15;6(6):793-801. doi: 10.1016/s0969-2126(98)00080-x.
Mucosal addressin cell adhesion molecule 1 (MAdCAM-1) is a cell adhesion molecule that is expressed on the endothelium in mucosa, and guides the specific homing of lymphocytes into mucosal tissues. MAdCAM-1 belongs to a subclass of the immunoglobulin superfamily (IgSF), the members of which are ligands for integrins. Human MAdCAM-1 has a unique dual function compared to other members in the same subclass in that it binds both the integrin alpha4beta7, through its two IgSF domains, and a selectin expressed on leukocytes, via carbohydrate sidechains. The structure determination of the two IgSF domains and comparison to the N-terminal two-domain structures of vascular cell adhesion molecule 1 (VCAM-1) and intercellular adhesion molecules (ICAM-1 and ICAM-2) allow us to assess the molecular basis of the interactions between integrins and their preferred ligands.
The crystal structure of a fragment containing the two IgSF domains of human MAdCAM-1 has been determined to 2.2 A resolution. The structure of MAdCAM-1 reveals two separate integrin-recognition motifs. The key integrin-binding residue, Asp42, resides in the CD loop of domain 1; a buried arginine residue (Arg70) plays a critical role in maintaining the conformation of this loop. The second binding site is associated with an unusual long D strand in domain 2. The D and E strands extend beyond the main body of the domain, forming a negatively charged beta ribbon unique to MAdCAM-1. This ribbon is located on the same face as the key aspartate residue in domain 1, consistent with evidence that it is involved in integrin binding.
The structural comparison of MAdCAM-1 to other members of the same IgSF subclass reveals some interesting features. Firstly, MAdCAM-1, like VCAM-1, has the key integrin-binding residue located on the protruding CD loop of domain 1 and binds to an integrin that lacks an I domain. This is in contrast to ICAM-1 and ICAM-2 where the key residue is located at the end of the C strand on a flat surface and which bind to integrins that contain I domains. Secondly, architectural differences in the CD loops of MAdCAM-1 and VCAM-1 cause an 8 A shift in position of the critical aspartate residue, and may partly determine their binding preference for different integrins. Finally, the unusual charge distribution of the two-domain fragment of MAdCAM-1 is predicted to orient the molecule optimally for integrin binding on the top of its long mucin-like stalk.
黏膜地址素细胞黏附分子1（MAdCAM - 1）是一种细胞黏附分子，表达于黏膜的内皮细胞上，引导淋巴细胞特异性归巢至黏膜组织。MAdCAM - 1属于免疫球蛋白超家族（IgSF）的一个亚类，该亚类成员是整合素的配体。与同一亚类的其他成员相比，人MAdCAM - 1具有独特的双重功能，即它通过其两个IgSF结构域与整合素α4β7结合，同时通过碳水化合物侧链与白细胞上表达的一种选择素结合。对这两个IgSF结构域进行结构测定，并与血管细胞黏附分子1（VCAM - 1）以及细胞间黏附分子（ICAM - 1和ICAM - 2）的N端两个结构域进行比较，使我们能够评估整合素与其首选配体之间相互作用的分子基础。
已确定包含人MAdCAM - 1两个IgSF结构域的片段的晶体结构，分辨率为2.2 Å。MAdCAM - 1的结构揭示了两个独立的整合素识别基序。关键的整合素结合残基Asp42位于结构域1的CD环中；一个埋藏的精氨酸残基（Arg70）在维持该环的构象中起关键作用。第二个结合位点与结构域2中一条异常长的D链相关。D链和E链延伸超出结构域的主体，形成了MAdCAM - 1特有的带负电荷的β折叠带。该折叠带与结构域1中的关键天冬氨酸残基位于同一面上，这与它参与整合素结合的证据一致。
MAdCAM - 1与同一IgSF亚类其他成员的结构比较揭示了一些有趣的特征。首先，MAdCAM - 1与VCAM - 1一样，关键的整合素结合残基位于结构域1突出的CD环上，并与缺乏I结构域的整合素结合。这与ICAM - 1和ICAM - 2不同，ICAM - 1和ICAM - 2的关键残基位于平坦表面上C链的末端，并与含有I结构域的整合素结合。其次，MAdCAM - 1和VCAM - 1的CD环在结构上的差异导致关键天冬氨酸残基位置有8 Å的偏移，这可能部分决定了它们对不同整合素的结合偏好。最后，预计MAdCAM - 1两结构域片段异常的电荷分布使其分子在其长的黏蛋白样茎的顶部以最佳方向进行整合素结合。
