AN UNUSUAL FEATURE REVEALED BY THE CRYSTAL-STRUCTURE AT 2.2-ANGSTROM RESOLUTION OF HUMAN TRANSFORMING GROWTH-FACTOR-BETA-2

TRANSFORMING growth factor type-beta-2 (TGF-beta-2)1 is a member of an expanding family of growth factors that regulate proliferation and differentiation of many different cell types2,3. TGF-beta-2 binds to various receptors4, one of which was shown to be a serine/threonine kinase5. TGF-beta-2 is involved in wound healing6, bone formation7 and modulation of immune functions8. We report here the crystal structure of TGF-beta-2 at 2.2 angstrom resolution, which reveals a novel monomer fold and dimer association. The monomer consists of two antiparallel pairs of beta-strands forming a flat curved surface and a separate, long alpha-helix. The disulphide-rich core has one disulphide bond pointing through a ring formed by the sequence motifs Cys-Ala-Gly-Ala-Cys and Cys-Lys-Cys, which are themselves connected through the cysteines. Two monomers are connected through a single disulphide bridge and associate such that the helix of one subunit interacts with the concave beta-sheet surface of the other. Four exposed loop regions might determine receptor specificity. The structure provides a suitable model for the TGF-beta-s and other members of the super-family9-11 and is the basis for the analysis of the TGF-beta-2 interactions with the receptor.