Abstract
Human calcium-sensing receptor (CaSR) is a G-protein-coupled receptor (GPCR) that maintains extracellular Ca(2+) homeostasis through the regulation of parathyroid hormone secretion. It functions as a disulfide-tethered homodimer composed of three main domains, the Venus Flytrap module, cysteine-rich domain, and seven-helix transmembrane region. Here, we present the crystal structures of the entire extracellular domain of CaSR in the resting and active conformations. We provide direct evidence that L-amino acids are agonists of the receptor. In the active structure, L-Trp occupies the orthosteric agonist-binding site at the interdomain cleft and is primarily responsible for inducing extracellular domain closure to initiate receptor activation. Our structures reveal multiple binding sites for Ca(2+) and PO4(3-) ions. Both ions are crucial for structural integrity of the receptor. While Ca(2+) ions stabilize the active state, PO4(3-) ions reinforce the inactive conformation. The activation mechanism of CaSR involves the formation of a novel dimer interface between subunits.
Highlights
The extracellular calcium-sensing receptor (CaSR) is responsible for the maintenance of a stable blood Ca2+ level (Brown et al, 1993; Hofer and Brown, 2003)
L-Trp, the amino acid used in this study, fits the role of an orthosteric agonist for CaSR. (1) It binds at the interdomain crevice of the Venus Flytrap (VFT) module, the canonical agonist-binding site for class C G-protein-coupled receptor (GPCR) (Geng et al, 2013; Kunishima et al, 2000; Muto et al, 2007; Tsuchiya et al, 2002)
A conserved serine residue is responsible for securing the carboxylate of L-Trp, glutamate and GABA in CaSR (S147), metabotropic glutamate receptors (mGluRs) (S165) (Kunishima et al, 2000) and GABAB receptor (S130) (Geng et al, 2013), respectively
Summary
The extracellular calcium-sensing receptor (CaSR) is responsible for the maintenance of a stable blood Ca2+ level (Brown et al, 1993; Hofer and Brown, 2003). It senses fluctuations in the circulating Ca2+ concentration and controls Ca2+ homeostasis by (1) modulating the production of parathyroid hormone in parathyroid glands, and (2) regulating the reabsorption of Ca2+ in kidney and bone (Brown, 2013). Abnormal function of CaSR is associated with Ca2+ homeostatic disorders (Brown, 2007; Hendy et al, 2009; Ward et al, 2012).
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