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Structure of human calcium-sensing receptor in complex with chimeric Gs (miniGis) protein in nanodiscs
Structural highlights
DiseaseCASR_HUMAN Autosomal dominant hypocalcemia;Familial isolated hypoparathyroidism due to impaired PTH secretion;Neonatal severe primary hyperparathyroidism;Familial hypocalciuric hypercalcemia type 1;Bartter syndrome with hypocalcemia. The disease is caused by mutations affecting the gene represented in this entry. The disease is caused by mutations affecting the gene represented in this entry. The disease is caused by mutations affecting the gene represented in this entry. Disease susceptibility is associated with variations affecting the gene represented in this entry. Homozygous defects in CASR can be a cause of primary hyperparathyroidism in adulthood. Patients suffer from osteoporosis and renal calculi, have marked hypercalcemia and increased serum PTH concentrations. FunctionCASR_HUMAN Senses changes in the extracellular concentration of calcium ions. The activity of this receptor is mediated by a G-protein that activates a phosphatidylinositol-calcium second messenger system. Publication Abstract from PubMedThe human calcium-sensing receptor (CaSR) detects fluctuations in the extracellular Ca(2+) concentration and maintains Ca(2+) homeostasis(1,2). It also mediates diverse cellular processes not associated with Ca(2+) balance(3-5). The functional pleiotropy of CaSR arises in part from its ability to signal through several G-protein subtypes(6). We determined structures of CaSR in complex with G proteins from three different subfamilies: G(q), G(i) and G(s). We found that the homodimeric CaSR of each complex couples to a single G protein through a common mode. This involves the C-terminal helix of each Galpha subunit binding to a shallow pocket that is formed in one CaSR subunit by all three intracellular loops (ICL1-ICL3), an extended transmembrane helix 3 and an ordered C-terminal region. G-protein binding expands the transmembrane dimer interface, which is further stabilized by phospholipid. The restraint imposed by the receptor dimer, in combination with ICL2, enables G-protein activation by facilitating conformational transition of Galpha. We identified a single Galpha residue that determines G(q) and G(s) versus G(i) selectivity. The length and flexibility of ICL2 allows CaSR to bind all three Galpha subtypes, thereby conferring capacity for promiscuous G-protein coupling. Promiscuous G-protein activation by the calcium-sensing receptor.,Zuo H, Park J, Frangaj A, Ye J, Lu G, Manning JJ, Asher WB, Lu Z, Hu GB, Wang L, Mendez J, Eng E, Zhang Z, Lin X, Grassucci R, Hendrickson WA, Clarke OB, Javitch JA, Conigrave AD, Fan QR Nature. 2024 May;629(8011):481-488. doi: 10.1038/s41586-024-07331-1. Epub 2024 , Apr 17. PMID:38632411[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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