Division of Structural Biology, Wellcome Centre for Human Genetics, Nuffield Department of Medicine, University of Oxford, Oxford, OX3 7BN, UK.
Faculty of Biology, Medicine and Health, University of Manchester, Manchester, M13 9PT, UK.
Nat Commun. 2024 Jun 11;15(1):4976. doi: 10.1038/s41467-024-49065-8.
Twisted gastrulation (TWSG1) is an evolutionarily conserved secreted glycoprotein which controls signaling by Bone Morphogenetic Proteins (BMPs). TWSG1 binds BMPs and their antagonist Chordin to control BMP signaling during embryonic development, kidney regeneration and cancer. We report crystal structures of TWSG1 alone and in complex with a BMP ligand, Growth Differentiation Factor 5. TWSG1 is composed of two distinct, disulfide-rich domains. The TWSG1 N-terminal domain occupies the BMP type 1 receptor binding site on BMPs, whereas the C-terminal domain binds to a Chordin family member. We show that TWSG1 inhibits BMP function in cellular signaling assays and mouse colon organoids. This inhibitory function is abolished in a TWSG1 mutant that cannot bind BMPs. The same mutation in the Drosophila TWSG1 ortholog Tsg fails to mediate BMP gradient formation required for dorsal-ventral axis patterning of the early embryo. Our studies reveal the evolutionarily conserved mechanism of BMP signaling inhibition by TWSG1.
扭曲胚层形成蛋白 1（TWSG1）是一种进化上保守的分泌型糖蛋白，可控制骨形态发生蛋白（BMPs）的信号转导。TWSG1 与 BMP 配体生长分化因子 5（Growth Differentiation Factor 5）结合，通过与 BMP 及其拮抗剂 Chordin 结合来控制胚胎发育、肾脏再生和癌症过程中的 BMP 信号转导。我们报告了 TWSG1 单独存在和与 BMP 配体结合的晶体结构。TWSG1 由两个不同的富含二硫键的结构域组成。TWSG1 的 N 端结构域占据 BMP 上的 BMP 型 1 受体结合位点，而 C 端结构域与 Chordin 家族成员结合。我们发现 TWSG1 在细胞信号转导测定和小鼠结肠类器官中抑制 BMP 功能。在不能结合 BMP 的 TWSG1 突变体中，这种抑制功能被消除。果蝇 TWSG1 同源物 Tsg 的相同突变不能介导早期胚胎背腹轴模式形成所必需的 BMP 梯度形成。我们的研究揭示了 TWSG1 抑制 BMP 信号转导的进化保守机制。
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