Crystal structure of BMP-9 and functional interactions with pro-region and receptors
Crystal structure of BMP-9 and functional interactions with pro-region and receptors
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DOI：
10.1074/jbc.m503328200
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发表时间：
2005-07-01
影响因子：
4.8
通讯作者：
Choe, S
中科院分区：
文献类型：
--
作者：
Brown, MA;Zhao, QH;Choe, S
骨形态发生蛋白（BMPs）是转化生长因子(TGF)- β超家族的一个子集，在发育和成人过程中调节多种细胞功能。BMP-9（也被称为生长和分化因子(GDF)-2）能诱导骨形成和软骨形成，与胆碱能神经元的分化有关，并可能有助于调节葡萄糖代谢。我们已经确定了BMP-9至2.3埃的结构，并检查了我们的模型与其他bmp的现有晶体结构之间的差异，无论是单独的还是与其受体复合的。tgf - β配体被翻译为前体，其前区通常在与配体切割后解离，但在某些情况下（包括GDF-8和tgf - β 1, 2和-3），前区在细胞分泌后仍然相关，并抑制配体与其受体的结合。虽然BMP-9的前区在分泌后仍然紧密相关，但我们发现，在几个基于细胞的实验中，BMP-9和BMP-9前区复合物的活性是相等的。激活素受体样激酶1 （ALK-1）是tgf - β家族中的孤儿受体，基于表面等离子体共振研究（BIAcore）和可溶性ALK-1阻断BMP-9前区复合物活性的能力，在基于细胞的分析中也被确定为BMP-9的潜在受体。
Bone morphogenetic proteins (BMPs), a subset of the transforming growth factor (TGF)-beta superfamily, regulate a diverse array of cellular functions during development and in the adult. BMP-9 (also known as growth and differentiation factor (GDF)-2) potently induces osteogenesis and chondrogenesis, has been implicated in the differentiation of cholinergic neurons, and may help regulate glucose metabolism. We have determined the structure of BMP-9 to 2.3 angstrom and examined the differences between our model and existing crystal structures of other BMPs, both in isolation and in complex with their receptors. TGF-beta ligands are translated as precursors, with pro-regions that generally dissociate after cleavage from the ligand, but in some cases (including GDF-8 and TGF-beta 1, -2, and -3), the pro-region remains associated after secretion from the cell and inhibits binding of the ligand to its receptor. Although the pro-region of BMP-9 remains tightly associated after secretion, we find, in several cell-based assays, that the activities of BMP-9 and BMP-9(.)pro-region complex were equivalent. Activin receptor-like kinase 1 (ALK-1), an orphan receptor in the TGF-beta family, was also identified as a potential receptor for BMP-9 based on surface plasmon resonance studies (BIAcore) and the ability of soluble ALK-1 to block the activity of BMP-9(.)pro-region complex in cell-based assays.