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hCG-receptor binding and transmembrane signaling
D Puett1, N Bhowmick, L M Fernandez
1Department of Biochemistry and Molecular Biology, University of Georgia, Athens 30602, USA. puett@bchiris.biochem.uga.edu
Molecular and Cellular Endocrinology
|December 20, 1996
Summary
Site-directed mutagenesis reveals key amino acids in human chorionic gonadotropin (hCG) and luteinizing hormone/chorionic gonadotropin receptor (LH/CG-R) interactions. These studies identify separate regions for binding and signaling, suggesting a ligand-induced receptor conformational change.
Area of Science:
- Biochemistry
- Molecular Biology
- Endocrinology
Background:
- Heterodimeric glycoprotein hormones interact with seven transmembrane G protein-coupled receptors.
- Site-directed mutagenesis is a powerful tool for studying these hormone-receptor interactions.
Purpose of the Study:
- Identify minimum core sequences for bioactivity of glycoprotein hormone subunits.
- Map amino acid residues on hCG and LH/CG-R critical for high-affinity binding.
- Determine receptor regions involved in transmembrane signaling.
Main Methods:
- Site-directed mutagenesis of hCG and LH/CG-R.
- Modeling studies based on crystal structures.
- Analysis of conserved ionizable amino acid residues in the extracellular domain (ECD) of LH/CG-R.
Main Results:
- Identified key amino acid residues on hCG and LH/CG-R for high-affinity binding, clustering on the hormone's surface.
- Mapped charged regions in the LH/CG-R ECD crucial for hormone recognition.
- Delineated specific receptor regions (ECD, extracellular loop III, TM helices VI and VII) involved in signaling but not binding.
Conclusions:
- Ligand binding and receptor activation are distinct but sequential processes.
- A ligand-induced conformational change, potentially involving TM helix reorientation, mediates receptor activation.