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Crystal structure of BMP-9 and functional interactions with pro-region and receptors.

The Journal of biological chemistry (2005-04-27)
Monica A Brown, Qinghai Zhao, Kent A Baker, Chethana Naik, Cecil Chen, Laurie Pukac, Mallika Singh, Tatiana Tsareva, Yanick Parice, Angela Mahoney, Viktor Roschke, Indra Sanyal, Senyon Choe
ABSTRACT

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 A 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-beta1, -2, and -3), the pro-region remains associated after secretion from the cell and inhibits binding of the ligand to its receptor. Although the proregion 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.

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Sigma-Aldrich
GDF-2 human, recombinant, expressed in CHO cells, ≥95% (SDS-PAGE), ≥95% (HPLC), suitable for cell culture