Dimeric Arrangement of the Parathyroid Hormone Receptor and a Structural Mechanism for Ligand-induced Dissociation

• Published in: The Journal of biological chemistry Vol. 285; no. 16; pp. 12435 - 12444
• Main Authors: Pioszak, Augen A., Harikumar, Kaleeckal G., Parker, Naomi R., Miller, Laurence J., Xu, H.Eric
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 16.04.2010; American Society for Biochemistry and Molecular Biology
• Subjects: Amino Acid Sequence; Amino Acid Substitution; Animals; Binding Sites; BIOLUMINESCENCE; Chlorocebus aethiops; COS Cells; CRYSTAL STRUCTURE; Crystallography, X-Ray; Cyclic AMP - metabolism; DIMERS; DISSOCIATION; ENERGY TRANSFER; FLUORESCENCE; Fluorescence Resonance Energy Transfer; G Protein-coupled Receptors (GPCR); HORMONES; Humans; HYPOTHESIS; In Vitro Techniques; Ligands; MATERIALS SCIENCE; Membrane Proteins; Models, Molecular; Molecular Sequence Data; Mutagenesis, Site-Directed; MUTATIONS; Osteoporosis; Parathyroid Hormone - metabolism; Parathyroid Hormone-Related Protein - metabolism; Peptide Hormones; Peptide Interactions; PEPTIDES; Protein Binding; Protein Multimerization; Protein Structure; Protein Structure, Quaternary; Protein Structure, Tertiary; PROTEINS; Receptor, Parathyroid Hormone, Type 1 - chemistry; Receptor, Parathyroid Hormone, Type 1 - genetics; Receptor, Parathyroid Hormone, Type 1 - metabolism; Recombinant Fusion Proteins - chemistry; Recombinant Fusion Proteins - genetics; Recombinant Fusion Proteins - metabolism; REGULATIONS; RESONANCE; Sequence Homology, Amino Acid; Signal Transduction; Transfection; Membrane Proteins; Osteoporosis; G Protein-coupled Receptors (GPCR); Peptide Hormones; Protein Structure; Peptide Interactions
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.M109.093138

The parathyroid hormone receptor (PTH1R) is a class B G protein-coupled receptor that is activated by parathyroid hormone (PTH) and PTH-related protein (PTHrP). Little is known about the oligomeric state of the receptor and its regulation by hormone. The crystal structure of the ligand-free PTH1R extracellular domain (ECD) reveals an unexpected dimer in which the C-terminal segment of both ECD protomers forms an α-helix that mimics PTH/PTHrP by occupying the peptide binding groove of the opposing protomer. ECD-mediated oligomerization of intact PTH1R was confirmed in living cells by bioluminescence and fluorescence resonance energy transfer experiments. As predicted by the structure, PTH binding disrupted receptor oligomerization. A receptor rendered monomeric by mutations in the ECD retained wild-type PTH binding and cAMP signaling ability. Our results are consistent with the hypothesis that PTH1R forms constitutive dimers that are dissociated by ligand binding and that monomeric PTH1R is capable of activating G protein.