Human Lutropin (hLH) and Choriogonadotropin (CG) are Assembled by Different Pathways: A Model of hLH Assembly [Protein Structure and Folding]

April 1st, 2014 by Bernard, M. P., Lin, W., Kholodovych, V., Moyle, W. R.

The glycoprotein hormones are all structurally related heterodimers consisting of an α-subunit and a ligand-specific β-subunit that confers their unique biological activity. Crystal structures showed how the β-subunit surrounds a part of the α-subunit, while we showed the existence of the two mechanisms responsible for that assembly. In human choriogonadotropin (hCG) the β-subunit is folded before the subunits dock and the α-subunit becomes incorporated into the dimer by a mechanism we termed "threading", passing between parts of the pre-assembled β-subunit. Here we show that the human lutropin (hLH) β-subunit is not folded prior to its interaction with the α-subunit and show that docking of the subunits enables the α-subunit to serve as a chaperone to the β-subunit. Based on data described here, we propose that the α-subunit facilitates formation of the hLHβ-subunit by two mechanisms. First, the cystine knot of the α-subunit potentiates formation of the β-subunit cystine knot and second, contacts between α-subunit loop 2 and a hydrophobic tail in the β-subunit facilitate formation of the seatbelt latch disulfide which stabilizes the heterodimer. The primary influence of the α-subunit was seen when the hydrophobic tail of the β-subunit was present or absent but the secondary mechanism was required only when the hydrophobic tail was present. During the evolution of hCG, neither of these α-subunit roles were necessary for folding the β-subunit. The complex mechanism for LH assembly may be required to provide an additional control on its positive feedback function in vertebrate reproduction.
  • Posted in Journal of Biological Chemistry, Publications
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