Five small protein domains, the CC-domains, at the N terminus of the RECK protein, play essential roles in signaling by WNT7A and WNT7B in the context of central nervous system angiogenesis and blood–brain barrier formation and maintenance. We have determined the structure of CC domain 4 (CC4) at 1.65-Å resolution and find that it folds into a compact four-helix bundle with three disulfide bonds. The CC4 structure, together with homology modeling of CC1, reveals the surface locations of critical residues that were shown in previous mutagenesis studies to mediate GPR124 binding and WNT7A/WNT7B recognition and signaling. Surprisingly, sequence and structural homology searches reveal no other cell-surface or secreted domains in vertebrates that resemble the CC domain, a pattern that is in striking contrast to other ancient and similarly sized domains, such as Epidermal Growth Factor, Fibronectin Type 3, Immunoglobulin, and Thrombospondin type 1 domains, which are collectively present in hundreds of proteins.

在中枢神经系统血管生成以及血脑屏障形成和维持的背景下，RECK蛋白N末端的五个小蛋白结构域CC结构域在WNT7A和WNT7B的信号传导中起重要作用。我们以1.65-Å的分辨率确定了CC域4（CC4）的结构，发现它折叠成带有三个二硫键的紧凑的四螺旋束。CC4结构以及CC1的同源性建模揭示了关键残基的表面位置，这些位置已在先前的诱变研究中介导GPR124结合以及WNT7A / WNT7B的识别和信号传导。令人惊讶的是，序列和结构同源性搜索没有显示出脊椎动物中其他类似CC结构域的细胞表面或分泌结构域，这种模式与其他古老且大小相似的结构域形成鲜明对比，