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Targeting Giants the Pharmacology of Adhesion Gpcrs

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Targeting Giants the Pharmacology of Adhesion Gpcrs Targeting Giants The Pharmacology of Adhesion GPCRs Torsten Schöneberg Rudolf Schönheimer Institute of Biochemistry Medical Faculty, University of Leipzig Leipzig, Germany The class of adhesion GPCRs G lutamate (Family C) R hodopsin (Family A) A dhesion (Family B) F rizzled/Taste2 S ecretin (Family B) Groups of adhesion GPCRs Hamann J., et al. Pharm Rev. 2015;67(2):338-67. Adhesion GPCR are giants among receptors Giants - > 750 Mio. years old - N terminus - up to 5,800 aa - C terminus - up to 450 aa - numerous interaction partners - numerous splice variants Evolution of aGPCRs and phenotypes in humans Signatures of recent selection Selection in human populations - GPR133 - GPR133 - GPR110, GPR111, GPR123 - GPR110, GPR111, GPR113 - GPR56, GPR64, GPR126 - GPR115, GPR64, GPR126 - EMR1, BAI1, CELSR1 … - EMR1, EMR3, BAI3 … QTL/SNP association GPR133 - height, weight, lipid, glucose, heart rate, myocardial infarction GPR126 - weight, lipid, glucose, insulin, height, pulmonary function … Kovacs P, Schöneberg T. Handb Exp Pharmacol. 2016;234:179-217. GPR133 promotes glioblastoma growth Bayin et al. Oncogenesis. 2016;5:e263. Adhesion GPCRs couple to G proteins SP HA tag P2Y12 N term. FLAG tag Human GPR133 Bohnekamp J, Schöneberg T. J Biol Chem. 2011;286:41912 Deletion of the N terminus initiates G-protein coupling GPR133 CTF P2Y12 CTF 800 SP n *** o HA tag i t 600 a l SP ] u t *** P2Y12 N term. w HA tag m f u o c 400 c a % [ P M 200 A c FLAG tag FLAG tag 0 t F F w T T C -C 2 Y 1 2 P Hypothetic scenarios of adhesion GPCR activation Ectodomain as tethered inverse agonist Ligand binding autoprot. cleavage Hypothetic scenarios of adhesion GPCR activation Ectodomain contains a tethered agonist Ligand binding autoprot. cleavage 800 n *** o i t 600 a l Deletion of the ectodomain activates GPR126 ] u t *** w m f u o c 400 c a % [ P M 200 A c 0 t F F F F w T T T T C -C -C -C 2 S S Y 1 P P 2 G G P Δ -Δ 2 Y 1 2 P Liebscher et al. Cell Rep. 2014;9:2018 -26. Peptide activation of GPR126 Peptide activation of GPR126 The ‚Stachel‘ Sequence EMR1 SSFAVLMAHYDVQ CD97 SSFAILMAHYDVE GPR56 TYFAVLMVSSVEV GPR114 TYFAVLMQLSGDP GPR115 TSFSILMSSKPVK GPR116 TSFSILMSPDSPD GPR126 THFGVLMDLPRSA GPR133 TNFAILMQVVPLE The ‚Stachel‘ Sequences of aGPCRs aGPCR Peptide length EC50 reference GPR126 16 AA > 400 µM Liebscher et al. (2014) Cell Rep GPR133 13 AA > 400 µM Liebscher et al. (2014) Cell Rep GPR56 7 AA 35 µM Stoveken et al. (2015) PNAS GPR110 10 AA 37 µM Stoveken et al. (2015) PNAS GPR64 15 AA 77 µM Demberg et al. (2015) BBRC GPR114 18 AA 100 µM Wilde et al. (2015) Faseb J Lat-1 12 AA Not determined Müller et al. (2015) PLoS Genet ‚Stachel‘ sequence in an aGPCR model GPR126 is a Gs protein-coupled receptor Mogha et al. J Neurosci. 2013; 33:17976-85. Rescue of myelination phenotype in GPR126-mutant zebrafish Stachel sequence Liebscher et al. Cell Rep. 2014;9:2018-26. Stachel peptide specificity Hamann J., et al. Pharm Rev. 2015;67(2):338-67. Stachel - derived peptide pcDps GPR64 GPR126specificity GPR110 30 *** , r 25 o t n c o e i *** t v a ) 20 l y *** e t u ** d Demberg Demberg p i t m m p u e 15 e c ** r c p * e a o v et al. et P n o 10 M d l A J o c f Biol - x ( 5 Chem. 2017 292:4383 2017 Chem. 0 pGPR64 - + - - - + - - - + - - - + - - pGPR126 - - + - - - + - - - + - - - + - pGPR110 - - - + - - - + - - - + - - - + - 94 Tethered agonism in GPCRs matrix proteins cell-cell contacts proteases mechanical force ? GPHs protease thyreostimulin relaxin LDLa TRAP p10 Stachel PARs GPHRs RXFP1 Adhesion GPCRs GPR126 is activated by shaking Petersen et al. Neuron 2015;85:755-69. Small Ligands of aGPCRs Gupte et al. FEBS Lett. 2012;586:1214-9. Antagonist at GPR56 and GPR114 Dihydromunduletone Stoveken et al. Mol Pharmacol. 2016;90:214-24. cis/trans signaling of adhesion GPCRs trans signaling (other partners) cis signaling (G proteins) (and others, e.g. ELMO/Dock) Acknowledgment University of Leipzig, Germany Ines Liebscher Julia Schön Lilian Demberg Caro Wilde Nina Auerbach Vera Lede Christin Schröck Simone Prömel Jana Winkler Antje Müller Charite Berlin, Germany Gunnar Kleinau Vollum Institute Portland, OR, USA Kelly Monk http://www.adhesiongpcr.org.
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