Structure of the parathyroid hormone receptor C terminus bound to the G-protein dimer Gbeta1gamma2.
A critical role of the Gbetagamma dimer in heterotrimeric G-protein signaling is to facilitate the engagement and activation of the Galpha subunit by cell-surface G-protein-coupled receptors. However, high-resolution structural information of the connectivity between receptor and the Gbetagamma dimer has not previously been available. Here, we describe the structural determinants of Gbeta1gamma2 in complex with a C-terminal region of the parathyroid hormone receptor-1 (PTH1R) as obtained by X-ray crystallography. The structure reveals that several critical residues within PTH1R contact only Gbeta residues located within the outer edge of WD1- and WD7-repeat segments of the Gbeta toroid structure. These regions encompass a predicted membrane-facing region of Gbeta thought to be oriented in a fashion that is accessible to the membrane-spanning receptor. Mutation of key receptor contact residues on Gbeta1 leads to a selective loss of function in receptor/heterotrimer coupling while preserving Gbeta1gamma2 activation of the effector phospholipase-C beta.
Johnston
Christopher A
CA
Department of Pharmacology, Lineberger Comprehensive Cancer Center and UNC Neuroscience Center, 1106 M.E. Jones Building, CB #7365, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
Kimple
Adam J
AJ
Giguère
Patrick M
PM
Siderovski
David P
DP
D000595:Amino Acid Sequence; D000818:Animals; D001665:Binding Sites; D019556:COS Cells; D002522:Chlorocebus aethiops; D018360:Crystallography, X-Ray; D019281:Dimerization; D044387:GTP-Binding Protein beta Subunits / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D044388:GTP-Binding Protein gamma Subunits / Q000737:chemistry* / Q000378:metabolism; D008958:Models, Molecular; D008969:Molecular Sequence Data; D016296:Mutagenesis; D044168:Receptor, Parathyroid Hormone, Type 1 / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D017386:Sequence Homology, Amino Acid
D044387:GTP-Binding Protein beta Subunits; D044388:GTP-Binding Protein gamma Subunits; D044168:Receptor, Parathyroid Hormone, Type 1