Abstract
G protein–coupled receptors (GPCRs) recruit β-arrestins to coordinate diverse cellular processes, but the structural dynamics driving this process are poorly understood. Atypical chemokine receptors (ACKRs) are intrinsically biased GPCRs that engage β-arrestins but not G proteins, making them a model system for investigating the structural basis of β-arrestin recruitment. Here, we performed nuclear magnetic resonance (NMR) experiments on 13CH3-ε–methionine–labeled ACKR3, revealing that β-arrestin recruitment is associated with conformational exchange at key regions of the extracellular ligand-binding pocket and intracellular β-arrestin–coupling region. NMR studies of ACKR3 mutants defective in β-arrestin recruitment identified an allosteric hub in the receptor core that coordinates transitions among heterogeneously populated and selected conformational states. Our data suggest that conformational selection guides β-arrestin recruitment by tuning receptor dynamics at intracellular and extracellular regions.
| Original language | English |
|---|---|
| Pages (from-to) | 222-228 |
| Number of pages | 7 |
| Journal | Science |
| Volume | 377 |
| Issue number | 6602 |
| Early online date | 7 Jul 2022 |
| DOIs | |
| Publication status | Published - 8 Jul 2022 |
Bibliographical note
Funding Information:This work was supported by the National Institutes of Health (grant F30CA196040 to A.B.K.; grant R01AI058072 to B.F.V.; grant F30HL134253 to M.A.T.; grant R35GM133421 to J.D.M.; and grant T32 GM080202 to the Medical Scientist Training Program at Medical College of Wisconsin to A.B.K. and M.A.T.); the State of Wisconsin Tax Check-Off Program for Cancer Research and the Medical College of Wisconsin Cancer Center (B.F.V.); the Luxembourg National Research Fund (Pathfinder “LIH383,” INTER/ FWO “Nanokine” grant 15/10358798 to A.C.); INTER/FNRS grants 20/15084569, PoC “Megakine” 19/14209621, AFR-3004509, and PRIDE 11012546 “NextImmune” to A.C.; F.R.S.-FNRS-Télévie grants 7.4593.19, 7.4529.19, and 7.8504.20 to A.C.; European Union’s Horizon 2020 MSCA Program (grant 641833 ONCORNET and 860229 ONCORNET2.0 to M.J.S.); American Lebanese Syrian Associated Charities (ALSAC grant to M.M.B.); and the UK Medical Research Council (MRC grant MC_U105185859 to M.M.B. and A.S.).
Publisher Copyright:
© 2022 American Association for the Advancement of Science. All rights reserved.
Funding
This work was supported by the National Institutes of Health (grant F30CA196040 to A.B.K.; grant R01AI058072 to B.F.V.; grant F30HL134253 to M.A.T.; grant R35GM133421 to J.D.M.; and grant T32 GM080202 to the Medical Scientist Training Program at Medical College of Wisconsin to A.B.K. and M.A.T.); the State of Wisconsin Tax Check-Off Program for Cancer Research and the Medical College of Wisconsin Cancer Center (B.F.V.); the Luxembourg National Research Fund (Pathfinder “LIH383,” INTER/ FWO “Nanokine” grant 15/10358798 to A.C.); INTER/FNRS grants 20/15084569, PoC “Megakine” 19/14209621, AFR-3004509, and PRIDE 11012546 “NextImmune” to A.C.; F.R.S.-FNRS-Télévie grants 7.4593.19, 7.4529.19, and 7.8504.20 to A.C.; European Union’s Horizon 2020 MSCA Program (grant 641833 ONCORNET and 860229 ONCORNET2.0 to M.J.S.); American Lebanese Syrian Associated Charities (ALSAC grant to M.M.B.); and the UK Medical Research Council (MRC grant MC_U105185859 to M.M.B. and A.S.).
| Funders | Funder number |
|---|---|
| European Union’s Horizon 2020 MSCA | 641833 ONCORNET, 860229 ONCORNET2.0 |
| State of Wisconsin Tax Check-Off Program for Cancer Research | |
| National Institutes of Health | F30CA196040, R01AI058072, T32 GM080202, R35GM133421 |
| National Heart, Lung, and Blood Institute | F30HL134253 |
| American Lebanese Syrian Associated Charities | |
| Medical College of Wisconsin Cancer Center | |
| Virginia Marine Resources Commission | MC_U105185859 |
| Medical Research Council | |
| Fonds National de la Recherche Luxembourg | LIH383 |
| Fonds Wetenschappelijk Onderzoek | 7.8504.20, 15/10358798, AFR-3004509, 11012546, 19/14209621, 20/15084569, 7.4593.19, 7.4529.19 |