The RGD finger of Del-1 is a unique structural feature critical for integrin binding
The RGD finger of Del-1 is a unique structural feature critical for integrin binding
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DOI：
10.1096/fj.11-202036
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发表时间：
2012-08-01
期刊：
影响因子：
4.8
通讯作者：
Wang, Jia-huai
中科院分区：
文献类型：
--
作者：
Schuerpf, Thomas;Chen, Qiang;Wang, Jia-huai
发育性内皮细胞基因座-1（Del-1）糖蛋白由内皮细胞和巨噬细胞亚群分泌。Del-1通过与整合素α（v）β 3相互作用，在血管重塑和先天免疫中起调节作用。Del-1含有3个表皮生长因子（EGF）样重复序列和2个盘状蛋白样结构域。第二EGF结构域（EGF 2）中的Arg-Gly-Asp（RGD）基序介导内皮细胞和吞噬细胞的粘附。我们报告了其3个EGF结构域的晶体结构。EGF 2的RGD基序在一个长的突出环的尖端形成一个II型β转角，称为RGD指。而EGF 2和EGF 3通过域间钙离子结合位点构成刚性杆，EGF 1和EGF 2之间的长接头赋予EGF 1相当大的灵活性。两个独特的O-连接聚糖和1个N-连接聚糖位于EGF 2与RGD基序的相反侧。这些结构特征有利于整合素与RGD指的结合。突变数据证实了在RGD指尖端具有RGD基序的重要性。对EGF结构域序列的数据库搜索显示，该RGD指状结构可能是Del-1的EGF结构域及其同源物乳脂球-EGF 8的进化插入和独特性。Schurpf，T.，陈昆，刘杰，王，R.，Springer，T.一、Wang，J. The RGD finger of Del-1 is a unique structure feature critical for integrin binding. FASEB J.26，3412-420（2012）. www.fasebj.org
Developmental endothelial cell locus-1 (Del-1) glycoprotein is secreted by endothelial cells and a subset of macrophages. Del-1 plays a regulatory role in vascular remodeling and functions in innate immunity through interaction with integrin alpha(v)beta 3. Del-1 contains 3 epidermal growth factor (EGF)-like repeats and 2 discoidin-like domains. An Arg-Gly-Asp (RGD) motif in the second EGF domain (EGF2) mediates adhesion by endothelial cells and phagocytes. We report the crystal structure of its 3 EGF domains. The RGD motif of EGF2 forms a type II' beta turn at the tip of a long protruding loop, dubbed the RGD finger. Whereas EGF2 and EGF3 constitute a rigid rod via an interdomain calcium ion binding site, the long linker between EGF1 and EGF2 lends considerable flexibility to EGF1. Two unique O-linked glycans and 1 N-linked glycan locate to the opposite side of EGF2 from the RGD motif. These structural features favor integrin binding of the RGD finger. Mutagenesis data confirm the importance of having the RGD motif at the tip of the RGD finger. A database search for EGF domain sequences shows that this RGD finger is likely an evolutionary insertion and unique to the EGF domain of Del-1 and its homologue milk fat globule-EGF 8.-Schurpf, T., Chen, Q., Liu, J., Wang, R., Springer, T. A., Wang, J. The RGD finger of Del-1 is a unique structural feature critical for integrin binding. FASEB J. 26, 3412-420 (2012). www.fasebj.org