CHIMERIC PROTEINS CAN EXCEED THE SUM OF THEIR PARTS - IMPLICATIONS FOR EVOLUTION AND PROTEIN DESIGN

Chimeric analogs derived from pairs of homologous proteins routinely e xhibit activities found in one or both parents, We describe chimeras o f two glycoprotein hormones, human chorionic gonadotropin (hCG) and hu man follitropin (hFSH), that exhibit activity unique to a third family member, human thyrotropin (hTSH). The results show that biological ac tivity can be separated from hormone-specific amino acid residues. Thi s is consistent with a model for the evolution of homologous ligand-re ceptor pairs involving gene duplication and the creation of inhibitory determinants that restrict binding. Disruption of these determinants can unmask activities characteristic of other members of a protein fam ily. Combining portions of two ligands to create analogs with properti es of a third family member can facilitate identifying key determinant s of protein-protein interaction and may be a useful strategy for crea ting novel therapeutics, In the case of the glycoprotein hormones, thi s showed that two different hormone regions (i.e., the seat-belt and t he intersubunit groove) appear to limit inappropriate contacts with re ceptors for other members of this family, These observations also have important caveats for chimera-based protein design because an unexpec ted gain of function may limit the therapeutic usefulness of some chim eras.