THE NOVEL FLIGHTLESS-I GENE BRINGS TOGETHER 2 GENE FAMILIES, ACTIN-BINDING PROTEINS RELATED TO GELSOLIN AND LEUCINE-RICH-REPEAT PROTEINS INVOLVED IN RAS SIGNAL-TRANSDUCTION

The Drosophila melanogaster gene flightless-I, involved in gastrulatio n and muscle degeneration, has Caenorhabditis elegans and human homolo gues. In these highly conserved genes, two previously known gene famil ies have been brought together, families encoding the actin-binding pr oteins related to gelsolin and the leucine-rich-repeat (LRR) group of proteins involved in protein-protein interactions. Both these gene fam ilies exhibit characteristics of molecular changes involving replicati on slippage and exon shuffling. Phylogenetic analyses of 19 amino acid sequences of 6 related protein types indicate that actin-associated p roteins related to gelsolin are monophyletic to a common ancestor and include flightless proteins. Conversely, comparison of 24 amino acid s equences of LRR proteins including the flightless proteins indicates t hat flightless proteins are members of a structurally related subgroup . Included in the flightless cluster are human and mouse rsp-1 protein s involved in suppressing v-Ras transformation of cells and the membra ne-associated yeast (Saccharomyces cerevisae) adenylate cyclase whose analogous LRRs are required for interaction with Ras proteins. There i s a strong possibility that ligands for this group could be related an d that flightless may have a similar role in Ras signal transduction. It is hypothesized that an ancestral monomeric gelsolin precursor prot ein has undergone at least four independent gene reorganization events to account for the structural diversity of the extant family of gelso lin-related proteins and that gene duplication and exon shuffling even ts occurred prior to or at the beginning of multicellular life, result ing in the evolution of some members of the family soon after the appe arance of actin-type proteins.