Structural basis of BMP signalling inhibition by the cystine knot protein Noggin
Structural basis of BMP signalling inhibition by the cystine knot protein Noggin
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DOI：
10.1038/nature01245
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发表时间：
2002-12-12
期刊：
影响因子：
64.8
通讯作者：
Choe, S
中科院分区：
文献类型：
--
作者：
Groppe, J;Greenwald, J;Choe, S
骨形态发生蛋白（BMPs）和它们的拮抗剂之间的相互作用支配着发育和细胞过程，如胚胎背腹轴的建立、神经组织的诱导、骨骼系统中关节的形成和成人大脑中的神经发生。迄今为止，BMP拮抗剂的三维结构和失活的结构基础仍然未知。在这里，我们报告的晶体结构的拮抗剂头蛋白结合到BMP-7，这表明头蛋白抑制BMP信号通过阻断分子界面的结合表位的I型和II型受体。BMP-7结合亲和力的位点特异性变异的头蛋白与骨形成和细胞凋亡在鸡肢体发育的变化，表明头蛋白的功能，螯合其配体在一个无活性的复合物。Noggin的支架含有与BMP类似的胱氨酸（半胱氨酸的氧化形式）结拓扑结构;因此，配体和拮抗剂似乎从共同的祖先基因进化而来。
The interplay between bone morphogenetic proteins (BMPs) and their antagonists governs developmental and cellular processes as diverse as establishment of the embryonic dorsal-ventral axis, induction of neural tissue, formation of joints in the skeletal system and neurogenesis in the adult brain. So far, the three-dimensional structures of BMP antagonists and the structural basis for inactivation have remained unknown. Here we report the crystal structure of the antagonist Noggin bound to BMP-7, which shows that Noggin inhibits BMP signalling by blocking the molecular interfaces of the binding epitopes for both type I and type II receptors. The BMP-7-binding affinity of site-specific variants of Noggin is correlated with alterations in bone formation and apoptosis in chick limb development, showing that Noggin functions by sequestering its ligand in an inactive complex. The scaffold of Noggin contains a cystine (the oxidized form of cysteine) knot topology similar to that of BMPs; thus, ligand and antagonist seem to have evolved from a common ancestral gene.