THE CRYSTAL-STRUCTURE OF TGF-BETA-3 AND COMPARISON TO TGF-BETA-2 - IMPLICATIONS FOR RECEPTOR-BINDING

Transforming growth factors beta belong to a group of cytokines that c ontrol cellular proliferation and differentiation. Five isoforms are k nown that share approximately 75% sequence identity,but exert differen t biological activities. The structure of TGF-beta 3 was solved by X-r ay crystallography and refined to a final R-factor of 17.5% at 2.0 Ang strom resolution. Comparison with the structure of TGF-beta 2 (Schlune gger MP, Grutter MG, 1992, Nature 358:430-434; Daopin S, Piez KA, Ogaw a Y, Davies DR, 1992, Science 257:369-373) reveals a virtually identic al central core. Differences exist in the conformations of the N-termi nal alpha-helix and in the beta-sheet loops. In TGF-beta 3, the N-term inal alpha-helix has moved approximate to 1 Angstrom away from the cen tral core. This movement can be correlated with the mutation of Leu 17 to Val and Ala 47 to Pro in TGF-beta 3. The beta-sheet loops rotate a s a rigid body 9 degrees around an axis that runs approximately parall el to the dimer axis. If these differences are recognized by the TGF-b eta receptors, they might account for the individual cellular response s. A molecule of the precipitating agent dioxane is bound in a crystal contact, forming a hydrogen bond with Trp 32. This dioxane may occupy a carbohydrate-binding site, because dioxane possesses some structura l similarity with a carbohydrate. The dioxane is in contact with two t ryptophans, which are often involved in carbohydrate recognition.