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 control cellular proliferation and differentiation. Five isoforms are known that share approximately 75% sequence identity, but exert different biological activities. The structure of TGF-beta 3 was solved by X-ray crystallography and refined to a final R-factor of 17.5% at 2.0 A resolution. Comparison with the structure of TGF-beta 2 (Schlunegger MP, Grütter MG, 1992, Nature 358:430-434; Daopin S, Piez KA, Ogawa Y, Davies DR, 1992, Science 257:369-373) reveals a virtually identical central core. Differences exist in the conformations of the N-terminal alpha-helix and in the beta-sheet loops. In TGF-beta 3, the N-terminal alpha-helix has moved approximately 1 A away from the central 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 as a rigid body 9 degrees around an axis that runs approximately parallel to the dimer axis. If these differences are recognized by the TGF-beta receptors, they might account for the individual cellular responses. 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 structural similarity with a carbohydrate. The dioxane is in contact with two tryptophans, which are often involved in carbohydrate recognition.
Mittl
P R
PR
Ciba-Geigy Ltd., Pharmaceutical Research, CH-4002 Basle, Switzerland.
Priestle
J P
JP
Cox
D A
DA
McMaster
G
G
Cerletti
N
N
Grütter
M G
MG
D000595:Amino Acid Sequence; D001704:Biopolymers; D018360:Crystallography, X-Ray; D004146:Dioxanes / Q000378:metabolism; D006801:Humans; D007536:Isomerism; D008969:Molecular Sequence Data; D011487:Protein Conformation; D018125:Receptors, Transforming Growth Factor beta / Q000378:metabolism*; D016415:Sequence Alignment; D016212:Transforming Growth Factor beta / Q000737:chemistry* / Q000378:metabolism
D001704:Biopolymers; D004146:Dioxanes; D018125:Receptors, Transforming Growth Factor beta; D016212:Transforming Growth Factor beta; C025223:1,4-dioxane