Design of stable biologically active recombinant lutropin analogs

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Abstract
Glycoprotein hormones are noncovalent heterodimers comprised of a common α subunit and a hormone-specific β subunit. Secretion and biologic action of these hormones are dependent on the formation of the heterodimer. The human LHβ subunit is unique among the other β subunits in that it assembles inefficiently with the α subunit. To bypass this rate-limiting step, we constructed the LH single chains where the carboxy terminus of β was fused to the amino terminus of α subunit through a linker. Compared to the human LH heterodimer, the extent of secretion was greater for the tethers although the rate was dependent on the nature of the linker. The LH single chains were biologically active even though there was loss of recognition by a LH-specific monoclonal antibody. This suggests that receptor binding of the single chains is not impaired by changes in the heterodimeric configuration resulting from tethering the subunits. In addition, single chains exhibited a remarkably greater in vitro stability than the heterodimer, implying that these analogs will be useful as diagnostic reagents and that their purification will be facilitated.