Chimeric proteins can exceed the sum of their parts: Implications for evolution and protein design

Department of OBGYN, Robert Wood Johnson (Rutgers) Medical School, Piscataway, NJ 08854, USA.
Nature Biotechnology (Impact Factor: 41.51). 06/1997; 15(5):439-43. DOI: 10.1038/nbt0597-439
Source: PubMed


Chimeric analogs derived from pairs of homologous proteins routinely exhibit activities found in one or both parents. We describe chimeras of two glycoprotein hormones, human chorionic gonadotropin (hCG) and human follitropin (hFSH), that exhibit activity unique to a third family member, human thyrotropin (hTSH). The results show that biological activity can be separated from hormone-specific amino acid residues. This is consistent with a model for the evolution of homologous ligand-receptor 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 family. Combining portions of two ligands to create analogs with properties of a third family member can facilitate identifying key determinants of protein-protein interaction and may be a useful strategy for creating novel therapeutics. In the case of the glycoprotein hormones, this showed that two different hormone regions (i.e., the seat-belt and the intersubunit groove) appear to limit inappropriate contacts with receptors for other members of this family. These observations also have important caveats for chimera-based protein design because an unexpected gain of function may limit the therapeutic usefulness of some chimeras.

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    • "between FSH (and thyroid-stimulating hormone, TSH) on the one hand, and LH (and chorionic gonadotropin, CG) on the other hand were thought to have separated FSHR-/TSHR-from LHR-activating properties (Campbell et al., 1997; Han et al., 1996). Further separation of specific FSH, TSH and LH activities has been shown by additional sequence divergence in the carboxy-terminal seatbelt segment as well as outside the seatbelt region (Grossmann et al., 1997). "
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    • "Like other chimeric proteins, Wld S has a biological activity that requires both of its parts. In other cases, this can be the result of a conformational change that confers a new property such as affi nity for a different receptor in the case of a ligand ( Campbell et al., 1997 ). The combination of two different proteins to form a chimera often arises from chromosome translocations or gene duplications and has evolutionary relevance. "
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    • "These studies revealed that the region between the 10th and 12th conserved cysteine residues (Cys 10–12 ; i.e. the seat-belt region) of each glycoprotein hormone ␤-subunit is critically involved in determining specificity for its respective receptor. In particular, the net charge differences in the determinant loop (i.e. the region between Cys 10 and Cys 11 ) of the seat-belt region between mammalian LH/CG ␤-subunits on the one hand, and FSH/TSH ␤-subunits on the other hand are thought to have partially separated LH-R-from FSH-R/TSH-R-activating properties (Han et al., 1996; Campbell et al., 1997). It is thought that additional sequence divergence in the carboxy-terminal seat-belt segment (i.e. between Cys 11 and Cys 12 ) as well as outside the seat-belt region has further separated specific lutropic, follitropic and thyrotropic activities of these hormones to their respective natural receptors (Grossmann et al., 1997). "
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