Receptor binding dependent structural changes in human choriogonadotropin: photochemical inter-subunit crosslinking

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Abstract
Activation of surface receptors is thought to occur in multiple transient steps with conformational adjustments of hormones and receptors beginning from the initial hormone-receptor contact. In this study, we have established a sensitive photochemical crosslinking method to detect structural change of hCG upon receptor binding. hCG consists of an α subunit and a β subunit. Free α subunit was derivatized with photosensitive reagents and reassociated with unmodified β subunit. Reassociated hCG αβ dimer was capable of high affinity receptor binding and activation. The reagents attached to the α subunit were capable of crosslinking the α subunit to the β subunit. However, the extent of inter-subunit cross-linking in solution was two-three fold greater than inter-subunit crosslinking after hCG bound to the receptor. This difference indicates a novel structural change at the subunit interface in response to hCG binding to the receptor. Although highly unlikely, other microenvironmental factors might have interfered with the crosslinking efficiency without impacting the structure of hCG. This study lays the ground work to precisely define the location and nature of the change. Such information will be crucial for the understanding of the molecular mechanism of the hormone-receptor interaction and receptor activation.