Identification of distant homologues of fibroblast growth factors suggestsa common ancestor for all beta-trefoil proteins

Determination of the structures of fibroblast growth factors and interleuki n-1s has previously revealed that they both adopt a beta-trefoil fold, simi lar to those found in Kunitz soybean trypsin inhibitors, ricin-like toxins, plant agglutinins and hisactophilin. These families possess distinct funct ions and occur in different subcellular localisations, and they appear to l ack significant similarities in their sequences, ligands and modes of ligan d binding. We have analysed the significance of sequence identities observe d after structure alignment and provide statistical evidence that these bet a-trefoil proteins are all homologues, having arisen from a common ancestor . Ln addition, we have explored the sequence space of all beta-trefoil prot eins and have determined that the actin-binding proteins fascins, and other proteins of unknown function, are beta-trefoil family homologues. Unlike o ther beta-trefoil proteins, the triplicated repeats in each of the four bet a-trefoil domains of fascins are significantly similar in sequence. This hi nts at how the beta-trefoil fold arose from the duplication of an ancestral gene encoding a homotrimeric single-repeat protein. The combined analysis of structure and sequence databases for detecting significant similarities is suggested as a highly sensitive approach to determining the common ances try of extremely divergent homologues. (C) 2000 Academic Press.