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Title: Viral GPCR US28 can signal in response to chemokine agonists of nearly unlimited structural degeneracy

Abstract

Human cytomegalovirus has hijacked and evolved a human G-protein-coupled receptor into US28, which functions as a promiscuous chemokine 'sink’ to facilitate evasion of host immune responses. To probe the molecular basis of US28’s unique ligand cross-reactivity, we deep-sequenced CX3CL1 chemokine libraries selected on ‘molecular casts’ of the US28 active-state and find that US28 can engage thousands of distinct chemokine sequences, many of which elicit diverse signaling outcomes. The structure of a G-protein-biased CX3CL1-variant in complex with US28 revealed an entirely unique chemokine amino terminal peptide conformation and remodeled constellation of receptor-ligand interactions. Receptor signaling, however, is remarkably robust to mutational disruption of these interactions. Thus, US28 accommodates and functionally discriminates amongst highly degenerate chemokine sequences by sensing the steric bulk of the ligands, which distort both receptor extracellular loops and the walls of the ligand binding pocket to varying degrees, rather than requiring sequence-specific bonding chemistries for recognition and signaling.

Authors:
ORCiD logo [1];  [2]; ORCiD logo [1]; ORCiD logo [1];  [1];  [3];  [1];  [2]; ORCiD logo [2];  [4];  [2]; ORCiD logo [5]
  1. Department of Molecular and Cellular Physiology, Stanford University School of Medicine, Stanford, United States; Department of Structural Biology, Stanford University School of Medicine, Stanford, United States
  2. Laboratory for Molecular Pharmacology, Department of Biomedical Sciences, Faculty of Health and Medical Science, University of Copenhagen, Denmark, Europe
  3. Department of Cancer Immunology and Virology, Dana Farber Cancer Institute, Boston, United States
  4. Program in Cellular and Molecular Medicine, Boston Children’s Hospital, Boston, United States
  5. Department of Molecular and Cellular Physiology, Stanford University School of Medicine, Stanford, United States; Department of Structural Biology, Stanford University School of Medicine, Stanford, United States; Howard Hughes Medical Institute, Stanford University School of Medicine, Stanford, United States
Publication Date:
Research Org.:
Argonne National Lab. (ANL), Argonne, IL (United States). Advanced Photon Source (APS)
Sponsoring Org.:
NIHAHAOTHERNIGMS
OSTI Identifier:
1459959
Resource Type:
Journal Article
Journal Name:
eLife
Additional Journal Information:
Journal Volume: 7; Journal Issue: 06, 2018; Journal ID: ISSN 2050-084X
Publisher:
eLife Sciences Publications, Ltd.
Country of Publication:
United States
Language:
ENGLISH

Citation Formats

Miles, Timothy F., Spiess, Katja, Jude, Kevin M., Tsutsumi, Naotaka, Burg, John S., Ingram, Jessica R., Waghray, Deepa, Hjorto, Gertrud M., Larsen, Olav, Ploegh, Hidde L., Rosenkilde, Mette M., and Garcia, K. Christopher. Viral GPCR US28 can signal in response to chemokine agonists of nearly unlimited structural degeneracy. United States: N. p., 2018. Web. doi:10.7554/eLife.35850.
Miles, Timothy F., Spiess, Katja, Jude, Kevin M., Tsutsumi, Naotaka, Burg, John S., Ingram, Jessica R., Waghray, Deepa, Hjorto, Gertrud M., Larsen, Olav, Ploegh, Hidde L., Rosenkilde, Mette M., & Garcia, K. Christopher. Viral GPCR US28 can signal in response to chemokine agonists of nearly unlimited structural degeneracy. United States. doi:10.7554/eLife.35850.
Miles, Timothy F., Spiess, Katja, Jude, Kevin M., Tsutsumi, Naotaka, Burg, John S., Ingram, Jessica R., Waghray, Deepa, Hjorto, Gertrud M., Larsen, Olav, Ploegh, Hidde L., Rosenkilde, Mette M., and Garcia, K. Christopher. Fri . "Viral GPCR US28 can signal in response to chemokine agonists of nearly unlimited structural degeneracy". United States. doi:10.7554/eLife.35850.
@article{osti_1459959,
title = {Viral GPCR US28 can signal in response to chemokine agonists of nearly unlimited structural degeneracy},
author = {Miles, Timothy F. and Spiess, Katja and Jude, Kevin M. and Tsutsumi, Naotaka and Burg, John S. and Ingram, Jessica R. and Waghray, Deepa and Hjorto, Gertrud M. and Larsen, Olav and Ploegh, Hidde L. and Rosenkilde, Mette M. and Garcia, K. Christopher},
abstractNote = {Human cytomegalovirus has hijacked and evolved a human G-protein-coupled receptor into US28, which functions as a promiscuous chemokine 'sink’ to facilitate evasion of host immune responses. To probe the molecular basis of US28’s unique ligand cross-reactivity, we deep-sequenced CX3CL1 chemokine libraries selected on ‘molecular casts’ of the US28 active-state and find that US28 can engage thousands of distinct chemokine sequences, many of which elicit diverse signaling outcomes. The structure of a G-protein-biased CX3CL1-variant in complex with US28 revealed an entirely unique chemokine amino terminal peptide conformation and remodeled constellation of receptor-ligand interactions. Receptor signaling, however, is remarkably robust to mutational disruption of these interactions. Thus, US28 accommodates and functionally discriminates amongst highly degenerate chemokine sequences by sensing the steric bulk of the ligands, which distort both receptor extracellular loops and the walls of the ligand binding pocket to varying degrees, rather than requiring sequence-specific bonding chemistries for recognition and signaling.},
doi = {10.7554/eLife.35850},
journal = {eLife},
issn = {2050-084X},
number = 06, 2018,
volume = 7,
place = {United States},
year = {2018},
month = {6}
}

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