Abstract
The canonical CGRP receptor is a complex between calcitonin receptor-like receptor (CLR), a family B G-protein-coupled receptor (GPCR) and receptor activity-modifying protein 1 (RAMP1). A third protein, receptor component protein (RCP) is needed for coupling to Gs. CGRP can interact with other RAMP–receptor complexes, particularly the AMY1 receptor formed between the calcitonin receptor (CTR) and RAMP1. Crystal structures are available for the binding of CGRP27–37 [D31,P34,F35] to the extracellular domain (ECD) of CLR and RAMP1; these show that extreme C-terminal amide of CGRP interacts with W84 of RAMP1 but the rest of the analogue interacts with CLR. Comparison with the crystal structure of a fragment of the allied peptide adrenomedullin bound to the ECD of CLR/RAMP2 confirms the importance of the interaction of the ligand C-terminus and the RAMP in determining pharmacology specificity, although the RAMPs probably also have allosteric actions. A cryo-electron microscope structure of calcitonin bound to the full-length CTR associated with Gs gives important clues as to the structure of the complete receptor and suggests that the N-terminus of CGRP makes contact with His5.40b, high on TM5 of CLR. However, it is currently not known how the RAMPs interact with the TM bundle of any GPCR. Major challenges remain in understanding how the ECD and TM domains work together to determine ligand specificity, and how G-proteins influence this and the role of RCP. It seems likely that allosteric mechanisms are particularly important as are the dynamics of the receptors.
Keywords
- Allostery
- Amylin
- Calcitonin
- Cryo-electron microscopy
- Crystallography
- Family B G-protein-coupled receptor
- Molecular dynamics
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References
Barwell J, Gingell JJ, Watkins HA, Archbold JK, Poyner DR, Hay DL (2012) Calcitonin and calcitonin receptor-like receptors: common themes with family B GPCRs? Br J Pharmacol 166(1):51–65
Barwell J, Wheatley M, Conner AC, Taddese B, Vohra S, Reynolds CA, Poyner DR (2013) The activation of the CGRP receptor. Biochem Soc Trans 41(1):180–184
Booe JM, Walker CS, Barwell J, Kuteyi G, Simms J, Jamaluddin MA, Warner ML, Bill RM, Harris PW, Brimble MA, Poyner DR, Hay DL, Pioszak AA (2015) Structural basis for receptor activity-modifying protein-dependent selective peptide recognition by a G protein-coupled receptor. Mol Cell 58(6):1040–1052
Booe JM, Warner ML, Roehrkasse AM, Hay DL, Pioszak AA (2018) Probing the mechanism of receptor activity-modifying protein modulation of GPCR ligand selectivity through rational design of potent adrenomedullin and calcitonin gene-related peptide antagonists. Mol Pharmacol 93:355
Conner M, Hicks MR, Dafforn T, Knowles TJ, Ludwig C, Staddon S, Overduin M, Gunther UL, Thome J, Wheatley M, Poyner DR, Conner AC (2008) Functional and biophysical analysis of the C-terminus of the CGRP-receptor; a family B GPCR. Biochemistry 47(32):8434–8444
Cordomi A, Liapakis G, Matsoukas MT (2017) Understanding Corticotropin Releasing Factor Receptor (CRFR) activation using structural models. Curr Mol Pharmacol 10(4):325–333
Dickerson IM (2013) Role of CGRP-receptor component protein (RCP) in CLR/RAMP function. Curr Protein Pept Sci 14(5):407–415
Evans BN, Rosenblatt MI, Mnayer LO, Oliver KR, Dickerson IM (2000) CGRP-RCP, a novel protein required for signal transduction at calcitonin gene-related peptide and adrenomedullin receptors. J Biol Chem 275(40):31438–31443
Gingell JJ, Simms J, Barwell J, Poyner DR, Watkins HA, Pioszak AA, Sexton PM, Hay DL (2016) An allosteric role for receptor activity-modifying proteins in defining GPCR pharmacology. Cell Discov 2:16012
Hay DL, Pioszak AA (2016) Receptor activity modifying proteins: new insights and roles. Annu Rev Pharmacol Toxicol 56:469
Hay DL, Poyner DR, Quirion R (2008) International Union of Pharmacology. LXIX. Status of the calcitonin gene-related peptide subtype 2 receptor. Pharmacol Rev 60(2):143–145
Hay DL, Garelja ML, Poyner DR, Walker CS (2017) Update on the pharmacology of calcitonin/CGRP family of peptides: IUPHAR Review 25. Br J Pharmacol 175(1):3–17
Ho HH, Gilbert MT, Nussenzveig DR, Gershengorn MC (1999) Glycosylation is important for binding to human calcitonin receptors. Biochemistry 38(6):1866–1872
Hu P, Wu S, Sun Y, Yuan CC, Kobayashi R, Myers MP, Hernandez N (2002) Characterization of human RNA polymerase III identifies orthologues for Saccharomyces cerevisiae RNA polymerase III subunits. Mol Cell Biol 22(22):8044–8055
Jazayeri A, Rappas M, Brown AJH, Kean J, Errey JC, Robertson NJ, Fiez-Vandal C, Andrews SP, Congreve M, Bortolato A, Mason JS, Baig AH, Teobald I, Dore AS, Weir M, Cooke RM, Marshall FH (2017) Crystal structure of the GLP-1 receptor bound to a peptide agonist. Nature 546(7657):254–258
Johansson E, Hansen JL, Hansen AM, Shaw AC, Becker P, Schaffer L, Reedtz-Runge S (2016) Type II turn of receptor-bound Salmon calcitonin revealed by X-ray crystallography. J Biol Chem 291(26):13689–13698
Johnson EC, Shafer OT, Trigg JS, Park J, Schooley DA, Dow JA, Taghert PH (2005) A novel diuretic hormone receptor in Drosophila: evidence for conservation of CGRP signaling. J Exp Biol 208(Pt 7):1239–1246
Kuwasako K, Cao YN, Chu CP, Iwatsubo S, Eto T, Kitamura K (2006) Functions of the cytoplasmic tails of the human receptor activity-modifying protein components of calcitonin gene-related peptide and adrenomedullin receptors. J Biol Chem 281(11):7205–7213
Kuwasako K, Kitamura K, Nagata S, Hikosaka T, Kato J (2010) Function of the cytoplasmic tail of human calcitonin receptor-like receptor in complex with receptor activity-modifying protein 2. Biochem Biophys Res Commun 392(3):380–385
Kuwasako K, Kitamura K, Nagata S, Hikosaka T, Kato J (2011) Structure-function analysis of helix 8 of human calcitonin receptor-like receptor within the adrenomedullin 1 receptor. Peptides 32(1):144–149
Kuwasako K, Hay DL, Nagata S, Hikosaka T, Kitamura K, Kato J (2012) The third extracellular loop of the human calcitonin receptor-like receptor is crucial for the activation of adrenomedullin signalling. Br J Pharmacol 166(1):137–150
Lee SM, Hay DL, Pioszak AA (2016) Calcitonin and amylin receptor peptide interaction mechanisms: insights into peptide-binding modes and allosteric modulation of the calcitonin receptor by receptor activity-modifying proteins. J Biol Chem 291(16):8686–8700
Lee SM, Booe JM, Gingell JJ, Sjoelund V, Hay DL, Pioszak AA (2017) N-glycosylation of asparagine 130 in the extracellular domain of the human calcitonin receptor significantly increases peptide hormone affinity. Biochemistry 56:3380
Liang YL, Khoshouei M, Radjainia M, Zhang Y, Glukhova A, Tarrasch J, Thal DM, Furness SGB, Christopoulos G, Coudrat T, Danev R, Baumeister W, Miller LJ, Christopoulos A, Kobilka BK, Wootten D, Skiniotis G, Sexton PM (2017) Phase-plate cryo-EM structure of a class B GPCR-G-protein complex. Nature 546(7656):118–123
Mallee JJ, Salvatore CA, LeBourdelles B, Oliver KR, Longmore J, Koblan KS, Kane SA (2002) Receptor activity-modifying protein 1 determines the species selectivity of non-peptide CGRP receptor antagonists. J Biol Chem 277(16):14294–14298
McLatchie LM, Fraser NJ, Main MJ, Wise A, Brown J, Thompson N, Solari R, Lee MG, Foord SM (1998) RAMPs regulate the transport and ligand specificity of the calcitonin-receptor-like receptor. Nature 393(6683):333–339
Morfis M, Tilakaratne N, Furness SG, Christopoulos G, Werry TD, Christopoulos A, Sexton PM (2008) Receptor activity-modifying proteins differentially modulate the G protein-coupling efficiency of amylin receptors. Endocrinology 149(11):5423–5431
Sardi C, Zambusi L, Finardi A, Ruffini F, Tolun AA, Dickerson IM, Righi M, Zacchetti D, Grohovaz F, Provini L, Furlan R, Morara S (2014) Involvement of calcitonin gene-related peptide and receptor component protein in experimental autoimmune encephalomyelitis. J Neuroimmunol 271(1–2):18–29
Sekiguchi T, Kuwasako K, Ogasawara M, Takahashi H, Matsubara S, Osugi T, Muramatsu I, Sasayama Y, Suzuki N, Satake H (2016) Evidence for conservation of the calcitonin superfamily and activity-regulating mechanisms in the basal chordate Branchiostoma floridae: insights into the molecular and functional evolution in chordates. J Biol Chem 291(5):2345–2356
Singh R, Ahalawat N, Murarka RK (2015) Activation of corticotropin-releasing factor 1 receptor: insights from molecular dynamics simulations. J Phys Chem B 119(7):2806–2817
ter Haar E, Koth CM, Abdul-Manan N, Swenson L, Coll JT, Lippke JA, Lepre CA, Garcia-Guzman M, Moore JM (2010) Crystal structure of the ectodomain complex of the CGRP receptor, a class-B GPCR, reveals the site of drug antagonism. Structure 18(9):1083–1093
Udawela M, Christopoulos G, Morfis M, Christopoulos A, Ye S, Tilakaratne N, Sexton PM (2006a) A critical role for the short intracellular C terminus in receptor activity-modifying protein function. Mol Pharmacol 70(5):1750–1760
Udawela M, Christopoulos G, Tilakaratne N, Christopoulos A, Albiston A, Sexton PM (2006b) Distinct receptor activity-modifying protein domains differentially modulate interaction with calcitonin receptors. Mol Pharmacol 69(6):1984–1989
Udawela M, Christopoulos G, Morfis M, Tilakaratne N, Christopoulos A, Sexton PM (2008) The effects of C-terminal truncation of receptor activity modifying proteins on the induction of amylin receptor phenotype from human CTb receptors. Regul Pept 145(1–3):65–71
Vohra S, Taddese B, Conner AC, Poyner DR, Hay DL, Barwell J, Reeves PJ, Upton GJ, Reynolds CA (2013) Similarity between class A and class B G-protein-coupled receptors exemplified through calcitonin gene-related peptide receptor modelling and mutagenesis studies. J R Soc Interface 10(79):20120846
Walker CS, Eftekhari S, Bower RL, Wilderman A, Insel PA, Edvinsson L, Waldvogel HJ, Jamaluddin MA, Russo AF, Hay DL (2015) A second trigeminal CGRP receptor: function and expression of the AMY1 receptor. Ann Clin Transl Neurol 2(6):595–608
Walker CS, Raddant AC, Woolley MJ, Russo AF, Hay DL (2017) CGRP receptor antagonist activity of olcegepant depends on the signalling pathway measured. Cephalalgia. https://doi.org/10.1177/0333102417691762
Watkins HA, Rathbone DL, Barwell J, Hay DL, Poyner DR (2013) Structure-activity relationships for alpha-calcitonin gene-related peptide. Br J Pharmacol 170(7):1308–1322
Watkins HA, Chakravarthy M, Abhayawardana RS, Gingell JJ, Garelja M, Pardamwar M, McElhinney JM, Lathbridge A, Constantine A, Harris PW, Yuen TY, Brimble MA, Barwell J, Poyner DR, Woolley MJ, Conner AC, Pioszak AA, Reynolds CA, Hay DL (2016) Receptor activity-modifying proteins 2 and 3 generate adrenomedullin receptor subtypes with distinct molecular properties. J Biol Chem 291(22):11657–11675
Weston C, Winfield I, Harris M, Hodgson R, Shah A, Dowell SJ, Mobarec JC, Woodcock DA, Reynolds CA, Poyner DR, Watkins HA, Ladds G (2016a) Receptor activity-modifying protein-directed G protein signaling specificity for the calcitonin gene-related peptide family of receptors. J Biol Chem 291(49):25763
Weston C, Winfield I, Harris M, Hodgson R, Shah A, Dowell SJ, Mobarec JC, Woodlock DA, Reynolds CA, Poyner DR, Watkins HA, Ladds G (2016b) Receptor activity-modifying protein-directed G protein signaling specificity for the calcitonin gene-related peptide family of receptors. J Biol Chem 291(42):21925–21944
Woolley MJ, Watkins HA, Taddese B, Karakullukcu ZG, Barwell J, Smith KJ, Hay DL, Poyner DR, Reynolds CA, Conner AC (2013) The role of ECL2 in CGRP receptor activation: a combined modelling and experimental approach. J R Soc Interface 10(88):20130589
Woolley MJ, Reynolds CA, Simms J, Walker CS, Mobarec JC, Garelja ML, Conner AC, Poyner DR, Hay DL (2017) Receptor activity-modifying protein dependent and independent activation mechanisms in the coupling of calcitonin gene-related peptide and adrenomedullin receptors to Gs. Biochem Pharmacol 142:96–110
Wootten D, Simms J, Miller LJ, Christopoulos A, Sexton PM (2013) Polar transmembrane interactions drive formation of ligand-specific and signal pathway-biased family B G protein-coupled receptor conformations. Proc Natl Acad Sci U S A 110:5211
Wootten D, Reynolds CA, Koole C, Smith KJ, Mobarec JC, Simms J, Quon T, Coudrat T, Furness SG, Miller LJ, Christopoulos A, Sexton PM (2016) A hydrogen-bonded polar network in the core of the glucagon-like peptide-1 receptor is a fulcrum for biased agonism: lessons from class B crystal structures. Mol Pharmacol 89(3):335–347
Zhang H, Qiao A, Yang D, Yang L, Dai A, de Graaf C, Reedtz-Runge S, Dharmarajan V, Zhang H, Han GW, Grant TD, Sierra RG, Weierstall U, Nelson G, Liu W, Wu Y, Ma L, Cai X, Lin G, Wu X, Geng Z, Dong Y, Song G, Griffin PR, Lau J, Cherezov V, Yang H, Hanson MA, Stevens RC, Zhao Q, Jiang H, Wang MW, Wu B (2017) Structure of the full-length glucagon class B G-protein-coupled receptor. Nature 546(7657):259–264
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This work was supported by the BBSRC (grant number BB/M007529/1).
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Simms, J., Routledge, S., Uddin, R., Poyner, D. (2018). The Structure of the CGRP and Related Receptors. In: Brain, S., Geppetti, P. (eds) Calcitonin Gene-Related Peptide (CGRP) Mechanisms. Handbook of Experimental Pharmacology, vol 255. Springer, Cham. https://doi.org/10.1007/164_2018_132
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DOI: https://doi.org/10.1007/164_2018_132
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