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

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

doi:10.7554/eLife.35850

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

Journal Article · Fri Jun 08 00:00:00 EDT 2018 · eLife

DOI:https://doi.org/10.7554/eLife.35850· OSTI ID:1459959

^[1]; Spiess, Katja ^[2]; ^[1]; ^[1]; Burg, John S. ^[1]; Ingram, Jessica R. ^[3]; Waghray, Deepa ^[1]; Hjorto, Gertrud M. ^[2]; ^[2]; Ploegh, Hidde L. ^[4]; Rosenkilde, Mette M. ^[2]; ^[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
Laboratory for Molecular Pharmacology, Department of Biomedical Sciences, Faculty of Health and Medical Science, University of Copenhagen, Denmark, Europe
Department of Cancer Immunology and Virology, Dana Farber Cancer Institute, Boston, United States
Program in Cellular and Molecular Medicine, Boston Children’s Hospital, Boston, United States
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

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.

Research Organization:: Advanced Photon Source (APS), Argonne National Laboratory (ANL), Argonne, IL (US)

Sponsoring Organization:: NIHAHAOTHERNIGMS

OSTI ID:: 1459959

Journal Information:: eLife, Journal Name: eLife Journal Issue: 06, 2018 Vol. 7; ISSN 2050-084X

Publisher:: eLife Sciences Publications, Ltd.

Country of Publication:: United States

Language:: ENGLISH

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