A docking site for G protein βγ subunits on the parathyroid hormone 1 receptor supports signaling through multiple pathways.
The G protein-coupled receptor for PTH and PTH-related protein (PTH1R) signals via many intracellular pathways. The purpose of this work is to investigate a G protein binding site on an intracellular domain of the PTH1R. The carboxy-terminal, cytoplasmic tail of the PTH1R fused to glutathione-S-transferase interacts with Gi/o proteins in ... vitro. All three subunits of the heterotrimer interact with the receptor C-tail. Activation of the heterotrimeric complex with GTPgammaS has no effect on Gbetagamma interactions, but markedly disrupts binding of the Galphai/o subunits to the receptor tail, suggesting that direct Gbetagamma binding indirectly links Galpha subunits to this region of the receptor. Gbetagamma subunits alone bind the C-tail with an affinity that is comparable to the heterotrimeric G protein complex. G protein complexes consisting of Galphashis6-beta1gamma2 and Galphaqhis6-beta1gamma2 also interact with the PTH1R tail in vitro. The Gbetagamma interaction domain is located on the juxta-membrane region of the tail between amino acids 468 and 491. Mutations that disrupt Gbetagamma interactions block PTH signaling via phospholipase Cbeta/[Ca2+]i and MAPK and markedly reduce signaling via adenylyl cyclase/cAMP. Herein, we define a domain on the PTH1R that is capable of binding G protein heterotrimeric complexes via direct Gbetagamma interactions.
Mesh Terms:
Adenylate Cyclase, Amino Acid Sequence, Animals, Binding Sites, Calcium, Cell Line, Cyclic AMP, Dimerization, GTP-Binding Protein beta Subunits, GTP-Binding Protein gamma Subunits, Guanosine 5'-O-(3-Thiotriphosphate), Humans, Isoenzymes, MAP Kinase Signaling System, Mice, Molecular Sequence Data, Mutation, Phospholipase C beta, Protein Binding, Protein Structure, Tertiary, Protein Subunits, Receptor, Parathyroid Hormone, Type 1, Signal Transduction, Type C Phospholipases
Adenylate Cyclase, Amino Acid Sequence, Animals, Binding Sites, Calcium, Cell Line, Cyclic AMP, Dimerization, GTP-Binding Protein beta Subunits, GTP-Binding Protein gamma Subunits, Guanosine 5'-O-(3-Thiotriphosphate), Humans, Isoenzymes, MAP Kinase Signaling System, Mice, Molecular Sequence Data, Mutation, Phospholipase C beta, Protein Binding, Protein Structure, Tertiary, Protein Subunits, Receptor, Parathyroid Hormone, Type 1, Signal Transduction, Type C Phospholipases
Mol. Endocrinol.
Date: Jan. 01, 2006
PubMed ID: 16099817
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