Department of Molecular Biology and Genetics, Johns Hopkins University School of Medicine, Baltimore, MD 21205.
HHMI, Johns Hopkins University School of Medicine, Baltimore, MD 21205.
Proc Natl Acad Sci U S A. 2023 May 16;120(20):e2217096120. doi: 10.1073/pnas.2217096120. Epub 2023 May 8.
Diverse extracellular proteins negatively regulate WNT signaling. One such regulator is adenomatosis polyposis coli down-regulated 1 (APCDD1), a conserved single-span transmembrane protein. In response to WNT signaling in a variety of tissues, transcripts are highly up-regulated. We have determined the three-dimensional structure of the extracellular domain of APCDD1, and this structure reveals an unusual architecture consisting of two closely apposed β-barrel domains (ABD1 and ABD2). ABD2, but not ABD1, has a large hydrophobic pocket that accommodates a bound lipid. The APCDD1 ECD can also bind to WNT7A, presumably via its covalently bound palmitoleate, a modification that is common to all WNTs and is essential for signaling. This work suggests that APCDD1 functions as a negative feedback regulator by titrating WNT ligands at the surface of responding cells.
多种细胞外蛋白负调控 WNT 信号通路。腺瘤性结肠息肉病基因下调蛋白 1（APCDD1）就是这样一种调控蛋白，它是一种保守的单跨膜蛋白。在多种组织中，当 WNT 信号通路被激活时， 转录本的表达水平会被高度上调。我们已经确定了 APCDD1 细胞外结构域的三维结构，该结构揭示了一种不寻常的架构，由两个紧密相邻的 β-桶结构域（ABD1 和 ABD2）组成。ABD2 而不是 ABD1 有一个大的疏水性口袋，可以容纳结合的脂质。APCDD1 的 ECD 还可以与 WNT7A 结合，可能是通过其共价结合的棕榈油酸，这种修饰是所有 WNT 共有的，对信号传递至关重要。这项工作表明，APCDD1 作为一种负反馈调节剂，通过在反应细胞表面滴定 WNT 配体来发挥作用。
