TOPOLOGICAL SIMILARITIES IN TGF-BETA-2, PDGF-BB AND NGF DEFINE A SUPERFAMILY OF POLYPEPTIDE GROWTH-FACTORS

Background: The development of functional diversity through gene dupli cation and subsequent divergent evolution can give rise to proteins th at have little or no sequence similarity, but retain similar topologie s. Results: The crystal structures of nerve growth factor, transformin g growth factor-beta 2 and platelet-derived growth factor-BB show that all three are based on a cystine-knot plus beta-strands topology. The re is very little sequence identity between the three proteins and the relationship between the structures had not been deduced from sequenc e comparisons. Each growth factor is usually active as a dimer; each e xists as a dimer in the crystal, but the relative orientations of the protomers are different in each case. Conclusion: The structural motif of disulphide bonds and hydrogen-bonded beta-strands unexpectedly fou nd in these three growth factors acts asa stable framework for elabora tion of loops of low sequence similarity that contain the specificity for receptor interaction.