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
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Ectodomain as tethered inverse agonist
Ligand binding autoprot. cleavage Hypothetic scenarios of adhesion GPCR activation
Ectodomain contains a tethered agonist
Ligand binding autoprot. cleavage Deletion of the ectodomain activates GPR126
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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 specificity
pcDps GPR64 GPR126 GPR110
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Demberg et al. J Biol Chem. 2017 292:4383-94 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