Leukocyte integrins αLβ2, αMβ2 and αXβ2 as collagen receptors-Receptor activation and recognition of GFOGER motif
Leukocyte integrins αLβ2, αMβ2 and αXβ2 as collagen receptors-Receptor activation and recognition of GFOGER motif
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DOI：
10.1016/j.biocel.2013.03.016
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发表时间：
2013-07-01
影响因子：
4
通讯作者：
Kapyla, Jarmo
中科院分区：
文献类型：
--
作者：
Lahti, Matti;Heino, Jyrki;Kapyla, Jarmo
整合素 α(L)β(2)、α(M)β(2) 和 α(X)β(2) 在白细胞上表达。它们的主要配体是反跨膜受体或血浆蛋白，例如细胞间细胞粘附分子-1 (ICAM-1) 或补体系统成分 (iC3b、iC4b)。这些整合素的功能阻断抗体也可能减少细胞对胶原蛋白的粘附。为了对作为胶原蛋白受体的人类α(L)β(2)、α(M)β(2)和α(X)β(2)进行首次系统比较，我们产生了野生型和活化形式的相应整合素αI结构域，并测量了它们与胶原蛋白I-VI的结合。在“闭合”（野生型）构象中，α I-L 和 α I-M 结构域与其主要配体以低亲和力结合，并且与胶原蛋白的相互作用也非常弱。功能获得性突变 alpha(L) I306G、alpha(L) K287C/K294C 和 alpha(M) I316G 被认为模拟“开放”、激活的 alpha I 结构域。这些激活的 α I 结构域与主要配体的结合明显更强，并且它们还以中等亲和力 (K-d < 400 nM) 识别胶原蛋白。激活后，与 IV 型胶原蛋白相比，α I-L 结构域有利于 I 型胶原蛋白（K-d 接近 0 nM）。整合素 α I-X 结构域以非常不同的方式发挥作用，因为它已经以天然野生型形式与胶原蛋白 IV 和 iC3b 结合（K-d 大约为 200-400 nM）。针对 alpha(X)beta(2) 和 alpha(M)beta(2) 的抗体可阻断早幼粒细胞白血病细胞与胶原 GFOGER 基序的粘附，该基序是含有胶原蛋白受体的 β(1) 整联蛋白的结合位点。简而言之，白细胞β(2)整合素可以以异二聚体特异性方式充当胶原蛋白受体。 (C) 2013 Elsevier Ltd. 保留所有权利。
Integrins alpha(L)beta(2), alpha(M)beta(2) and alpha(X)beta(2) are expressed on leukocytes. Their primary ligands are counter transmembrane receptors or plasma proteins, such as intercellular cell adhesion molecule-1 (ICAM-1) or components of complement system (iC3b, iC4b), respectively. Function blocking antibodies for these integrins may also reduce cell adhesion to collagens. To make the first systematical comparison of human alpha(L)beta(2), alpha(M)beta(2) and alpha(X)beta(2) as collagen receptors, we produced the corresponding integrin alpha I domains both in wild-type and activated form and measured their binding to collagens I-VI. In the "closed" (wild-type) conformation, the alpha I-L and alpha I-M domains bound with low avidity to their primary ligands, and the interaction with collagens was also very weak. Gain-of-function mutations alpha(L) I306G, alpha(L) K287C/K294C and alpha(M) I316G are considered to mimic "open", activated alpha I domains. The binding of these activated alpha I domains to the primary ligands was clearly stronger and they also recognized collagens with moderate avidity (K-d < 400 nM). After activation, the alpha I-L domain favored collagen I (K-d approximate to 0 nM) when compared to collagen IV. The integrin alpha I-X domain acted in a very different manner since already in native, wild-type form it bound to collagen IV and iC3b (K-d approximate to 200-400 nM). Antibodies against alpha(X)beta(2) and alpha(M)beta(2) blocked promyelocytic leukemia cell adhesion to the collagenous GFOGER motif, a binding site for the beta(1) integrin containing collagen receptors. In brief, leukocyte beta(2) integrins may act as collagen receptors in a heterodimer specific manner. (C) 2013 Elsevier Ltd. All rights reserved.