Groppe Jay, Greenwald Jason, Wiater Ezra, Rodriguez-Leon Joaquin, Economides Aris N, Kwiatkowski Witek, Affolter Markus, Vale Wylie W, Izpisua Belmonte Juan Carlos, Choe Senyon
Structural Biology, Salk Institute, 10010 North Torrey Pines Road, La Jolla, California 92037, USA.
Nature. 2002 Dec 12;420(6916):636-42. doi: 10.1038/nature01245.
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.
骨形态发生蛋白（BMPs）与其拮抗剂之间的相互作用调控着多种发育和细胞过程，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以及成人大脑中的神经发生。到目前为止，BMP拮抗剂的三维结构以及失活的结构基础仍不清楚。在此，我们报道了与BMP-7结合的拮抗剂头蛋白（Noggin）的晶体结构，该结构表明Noggin通过阻断I型和II型受体结合表位的分子界面来抑制BMP信号传导。Noggin位点特异性变体与BMP-7的结合亲和力与鸡肢体发育中骨形成和细胞凋亡的改变相关，表明Noggin通过将其配体隔离在无活性复合物中发挥作用。Noggin的支架包含一个与BMPs类似的胱氨酸（半胱氨酸的氧化形式）结拓扑结构；因此，配体和拮抗剂似乎是从一个共同的祖先基因进化而来的。
