COMPLEX FLEXIBILITY OF THE TRANSFORMING GROWTH-FACTOR-BETA SUPERFAMILY

The transforming growth factors beta (TGF-beta s) are important modula tors of growth and differentiation. They are intermolecular disulfide- bonded homodimeric molecules, The monomer fold has a conserved cystine knot and lacks a hydrophobic core. The biological specificity of a gi ven member of the family is believed to be determined by the conformat ional flexibility of the variable loop regions of the monomer, The mon omer subunit assembly in the dimer is stabilized mainly by hydrophobic contacts and a few hydrogen bonds, Since these interactions are nondi rectional, we examined subunit assemblies of TGF-beta by using conform ational analysis. The different subunit assemblies in TGF-beta 2 dimer were characterized in terms of the intersubunit disulfide torsion, Ou r analyses show that the subunit assemblies fall into two states: the crystallographically observed gauche + conformation and the previously not reported gauche - conformation, both having almost identical inte raction energies, Furthermore, there is significant flexibility in the subunit assembly within the gnuche + and the gauche - states of the d isulfide bond, The monomer subunit assembly is independent of the vari ations about the loop regions, The variations in the loop regions, cou pled with flexibility in the monomer assembly, lead to a complex flexi bility in the dimer of the TGF-beta superfamily, For the TGF-beta supe rfamily, the cystine knot acts as a scaffold and complex flexibility p rovides for biological selectivity. Complex flexibility might provide an explanation for the diverse range of biological activities that the se important molecules display.