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J Biol Chem

Title:		Delineating a Ca2+ binding pocket within the venus flytrap module of the human calcium-sensing receptor
Author(s):		Silve C; Petrel C; Leroy C; Bruel H; Mallet E; Rognan D; Ruat M;
Address:		"INSERM, U426, Faculte deMedecine Xavier Bichat and IFR02, Paris, France"
Journal Title:		J Biol Chem
Year:		2005
Volume:		20050907
Issue:		45
Page Number:		37917 - 37923
DOI:		10.1074/jbc.M506263200
ISSN/ISBN:		0021-9258 (Print) 0021-9258 (Linking)
Abstract:		"The Ca(2+)-sensing receptor (CaSR) belongs to the class III G-protein-coupled receptors (GPCRs), which include receptors for pheromones, amino acids, sweeteners, and the neurotransmitters glutamate and gamma-aminobutyric acid (GABA). These receptors are characterized by a long extracellular amino-terminal domain called a Venus flytrap module (VFTM) containing the ligand binding pocket. To elucidate the molecular determinants implicated in Ca(2+) recognition by the CaSR VFTM, we developed a homology model of the human CaSR VFTM from the x-ray structure of the metabotropic glutamate receptor type 1 (mGluR1), and a phylogenetic analysis of 14 class III GPCR VFTMs. We identified critical amino acids delineating a Ca(2+) binding pocket predicted to be adjacent to, but distinct from, a cavity reminiscent of the binding site described for amino acids in mGluRs, GABA-B receptor, and GPRC6a. Most interestingly, these Ca(2+)-contacting residues are well conserved within class III GPCR VFTMs. Our model was validated by mutational and functional analysis, including the characterization of activating and inactivating mutations affecting a single amino acid, Glu-297, located within the proposed Ca(2+) binding pocket of the CaSR and associated with autosomal dominant hypocalcemia and familial hypocalciuric hypercalcemia, respectively, genetic diseases characterized by perturbations in Ca(2+) homeostasis. Altogether, these data define a Ca(2+) binding pocket within the CaSR VFTM that may be conserved in several other class III GPCRs, thereby providing a molecular basis for extracellular Ca(2+) sensing by these receptors"
Keywords:		"Amino Acid Sequence Animals Base Sequence Binding Sites Calcium/*metabolism Female Humans Male Mutation Pedigree Phylogeny Rats Receptors, AMPA/metabolism Receptors, Calcium-Sensing/*chemistry/genetics/*metabolism;"
Notes:		"MedlineSilve, Caroline Petrel, Christophe Leroy, Christine Bruel, Henri Mallet, Eric Rognan, Didier Ruat, Martial eng Research Support, Non-U.S. Gov't 2005/09/09 J Biol Chem. 2005 Nov 11; 280(45):37917-23. doi: 10.1074/jbc.M506263200. Epub 2005 Sep 7"