EVOLUTIONARY CONSERVATION AND PREDICTED STRUCTURE OF THE DROSOPHILA EXTRA SEX COMBS REPRESSOR PROTEIN

The Drosophila extra sex combs (esc) protein, a member of the Polycomb group (PcG), is a transcriptional repressor of homeotic genes, Geneti c studies have shown that esc protein is required in early embryos at about the time that other PcG proteins become engaged in homeotic gene repression. The esc protein consists primarily of multiple copies of the WD repeat, a motif that has been implicated in protein-protein int eraction. To further investigate the domain organization of esc protei n, we have isolated and characterized esc homologs from divergent inse ct species. We report that esc protein is highly conserved in housefly (72% identical to Drosophila esc), butterfly (55% identical), and gra sshopper (56% identical). We show that the butterfly homolog provides esc function in Drosophila, indicating that the sequence similarities reflect functional conservation. Homology modeling using the crystal s tructure of another WD repeat protein, the G-protein beta-subunit, pre dicts that esc protein adopts a beta-propeller structure. The sequence comparisons and modeling suggest that there are seven WD repeats in e sc protein which together form a seven-bladed beta-propeller. We locat e the conserved regions in esc protein with respect to this predicted structure. Site-directed mutagenesis of specific loops, predicted to e xtend from the propeller surface, identifies conserved parts of esc pr otein required for function in vivo. We suggest that these regions mig ht mediate physical interaction with esc partner proteins.