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Structural mechanism of cooperative activation of the human calcium-sensing receptor by Ca2+ ions and L-tryptophan.

<div class='caption-title'>Cryo-EM structures of CaSR in active and inactive states.</div>
<div class='caption-title'>Cryo-EM structure of CaSR in the L-Trp-bound state.</div>
<div class='caption-title'>Cryo-EM structure of CaSR in the Ca2+-bound state.</div>
Ling S, Shi P, Liu S, Meng X, Zhou Y, Sun W, Chang S, Zhang X, Zhang L, Shi C, Sun D, Liu L, Tian C
OpenAccess logo Cell Res 31 383-394 (2021)
Related entries: 7dtu, 7dtv, 7dtw

Cited: 18 times
EuropePMC logo PMID: 33603117

Abstract

The human calcium-sensing receptor (CaSR) is a class C G protein-coupled receptor (GPCR) responsible for maintaining Ca2+ homeostasis in the blood. The general consensus is that extracellular Ca2+ is the principal agonist of CaSR. Aliphatic and aromatic L-amino acids, such as L-Phe and L-Trp, increase the sensitivity of CaSR towards Ca2+ and are considered allosteric activators. Crystal structures of the extracellular domain (ECD) of CaSR dimer have demonstrated Ca2+ and L-Trp binding sites and conformational changes of the ECD upon Ca2+/L-Trp binding. However, it remains to be understood at the structural level how Ca2+/L-Trp binding to the ECD leads to conformational changes in transmembrane domains (TMDs) and consequent CaSR activation. Here, we determined the structures of full-length human CaSR in the inactive state, Ca2+- or L-Trp-bound states, and Ca2+/L-Trp-bound active state using single-particle cryo-electron microscopy. Structural studies demonstrate that L-Trp binding induces the closure of the Venus flytrap (VFT) domain of CaSR, bringing the receptor into an intermediate active state. Ca2+ binding relays the conformational changes from the VFT domains to the TMDs, consequently inducing close contact between the two TMDs of dimeric CaSR, activating the receptor. Importantly, our structural and functional studies reveal that Ca2+ ions and L-Trp activate CaSR cooperatively. Amino acids are not able to activate CaSR alone, but can promote the receptor activation in the presence of Ca2+. Our data provide complementary insights into the activation of class C GPCRs and may aid in the development of novel drugs targeting CaSR.

Reviews - 7dtt mentioned but not cited (1)

  1. G protein-coupled receptors in neurodegenerative diseases and psychiatric disorders. Wong TS, Li G, Li S, Gao W, Chen G, Gan S, Zhang M, Li H, Wu S, Du Y. Signal Transduct Target Ther 8 177 (2023)

Articles - 7dtt mentioned but not cited (2)

  1. In Vitro and In Silico Investigation of BCI Anticancer Properties and Its Potential for Chemotherapy-Combined Treatments. Marciniak B, Kciuk M, Mujwar S, Sundaraj R, Bukowski K, Gruszka R. Cancers (Basel) 15 4442 (2023)
  2. Mechanism of sensitivity modulation in the calcium-sensing receptor via electrostatic tuning. Schamber MR, Vafabakhsh R. Nat Commun 13 2194 (2022)


Reviews citing this publication (2)

  1. Extracellular Calcium Receptor as a Target for Glutathione and Its Derivatives. Goralski T, Ram JL. Int J Mol Sci 23 717 (2022)
  2. Membranes under the Magnetic Lens: A Dive into the Diverse World of Membrane Protein Structures Using Cryo-EM. Piper SJ, Johnson RM, Wootten D, Sexton PM. Chem Rev 122 13989-14017 (2022)

Articles citing this publication (13)

  1. Structural insights into the activation of human calcium-sensing receptor. Chen X, Wang L, Cui Q, Ding Z, Han L, Kou Y, Zhang W, Wang H, Jia X, Dai M, Shi Z, Li Y, Li X, Geng Y. Elife 10 e68578 (2021)
  2. Symmetric activation and modulation of the human calcium-sensing receptor. Park J, Zuo H, Frangaj A, Fu Z, Yen LY, Zhang Z, Mosyak L, Slavkovich VN, Liu J, Ray KM, Cao B, Vallese F, Geng Y, Chen S, Grassucci R, Dandey VP, Tan YZ, Eng E, Lee Y, Kloss B, Liu Z, Hendrickson WA, Potter CS, Carragher B, Graziano J, Conigrave AD, Frank J, Clarke OB, Fan QR. Proc Natl Acad Sci U S A 118 e2115849118 (2021)
  3. Allosteric ligands control the activation of a class C GPCR heterodimer by acting at the transmembrane interface. Liu L, Fan Z, Rovira X, Xue L, Roux S, Brabet I, Xin M, Pin JP, Rondard P, Liu J. Elife 10 e70188 (2021)
  4. Calcium sensing receptor stimulates breast cancer cell migration via the Gβγ-AKT-mTORC2 signaling pathway. Orduña-Castillo LB, Del-Río-Robles JE, García-Jiménez I, Zavala-Barrera C, Beltrán-Navarro YM, Hidalgo-Moyle JJ, Ramírez-Rangel I, Hernández-Bedolla MA, Reyes-Ibarra AP, Valadez-Sánchez M, Vázquez-Prado J, Reyes-Cruz G. J Cell Commun Signal 16 239-252 (2022)
  5. Cholesterol in Class C GPCRs: Role, Relevance, and Localization. Isu UH, Badiee SA, Khodadadi E, Moradi M. Membranes (Basel) 13 301 (2023)
  6. Coordination chemogenetics for activation of GPCR-type glutamate receptors in brain tissue. Ojima K, Kakegawa W, Yamasaki T, Miura Y, Itoh M, Michibata Y, Kubota R, Doura T, Miura E, Nonaka H, Mizuno S, Takahashi S, Yuzaki M, Hamachi I, Kiyonaka S. Nat Commun 13 3167 (2022)
  7. Global genetic diversity, introgression, and evolutionary adaptation of indicine cattle revealed by whole genome sequencing. Chen N, Xia X, Hanif Q, Zhang F, Dang R, Huang B, Lyu Y, Luo X, Zhang H, Yan H, Wang S, Wang F, Chen J, Guan X, Liu Y, Li S, Jin L, Wang P, Sun L, Zhang J, Liu J, Qu K, Cao Y, Sun J, Liao Y, Xiao Z, Cai M, Mu L, Siddiki AZ, Asif M, Mansoor S, Babar ME, Hussain T, Silva GLLP, Gorkhali NA, Terefe E, Belay G, Tijjani A, Zegeye T, Gebre MG, Ma Y, Wang Y, Huang Y, Lan X, Chen H, Migliore NR, Colombo G, Semino O, Achilli A, Sinding MS, Lenstra JA, Cheng H, Lu W, Hanotte O, Han J, Jiang Y, Lei C. Nat Commun 14 7803 (2023)
  8. Molecular dynamics study of tropical calcific pancreatitis (TCP) associated calcium-sensing receptor single nucleotide variation. Shrivastava A, Mathur K, Verma RK, Jayadev Magani SK, Vyas DK, Singh A. Front Mol Biosci 9 982831 (2022)
  9. Radiofrequency Ablation of Parathyroid Glands to Treat a Patient With Hypercalcemia Caused by a Novel Inactivating Mutation in CaSR. Hao Y, Lei Z, Shi N, Yu L, Ji W, Zhang X. Front Endocrinol (Lausanne) 12 743517 (2021)
  10. Letter Structural basis of the activation of metabotropic glutamate receptor 3. Fang W, Yang F, Xu C, Ling S, Lin L, Zhou Y, Sun W, Wang X, Liu P, Rondard P, Shi P, Pin JP, Tian C, Liu J. Cell Res 32 695-698 (2022)
  11. Letter Structural insights into asymmetric activation of the calcium-sensing receptor-Gq complex. Ling S, Meng X, Zhang Y, Xia Z, Zhou Y, Yang F, Shi P, Shi C, Tian C. Cell Res (2023)
  12. Structure of the class C orphan GPCR GPR158 in complex with RGS7-Gβ5. Jeong E, Kim Y, Jeong J, Cho Y. Nat Commun 12 6805 (2021)
  13. The Amino Acids Sensing and Utilization in Response to Dietary Aromatic Amino Acid Supplementation in LPS-Induced Inflammation Piglet Model. Duanmu Q, Tan B, Wang J, Huang B, Li J, Kang M, Huang K, Deng Q, Yin Y. Front Nutr 8 819835 (2021)


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