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

Timothy F. Miles; Katja Spiess; Kevin M. Jude; Naotaka Tsutsumi; John S. Burg; Jessica R. Ingram; Deepa Waghray; Gertrud M. Hjorto; Olav Larsen; Hidde L. Ploegh; Mette M. Rosenkilde; K. Christopher Garcia

doi:10.7554/eLife.35850

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

Timothy F. Miles, Katja Spiess, Kevin M. Jude, Naotaka Tsutsumi, John S. Burg, Jessica R. Ingram, Deepa Waghray, Gertrud M. Hjorto, Olav Larsen, Hidde L. Ploegh, Mette M. Rosenkilde, K. Christopher Garcia

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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

Original language	English
Article number	e35850
Journal	eLife
Volume	7
Number of pages	23
ISSN	2050-084X
DOIs	https://doi.org/10.7554/eLife.35850
Publication status	Published - 8 Jun 2018

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Cite this

@article{e818a46a8a72458783fff680fb5dd99b,

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",

author = "Miles, {Timothy F.} and Katja Spiess and Jude, {Kevin M.} and Naotaka Tsutsumi and Burg, {John S.} and Ingram, {Jessica R.} and Deepa Waghray and Hjorto, {Gertrud M.} and Olav Larsen and Ploegh, {Hidde L.} and Rosenkilde, {Mette M.} and Garcia, {K. Christopher}",

year = "2018",

month = jun,

day = "8",

doi = "10.7554/eLife.35850",

language = "English",

volume = "7",

journal = "eLife",

issn = "2050-084X",

publisher = "eLife Sciences Publications Ltd.",

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TY - JOUR

T1 - Viral GPCR US28 can signal in response to chemokine agonists of nearly unlimited structural degeneracy

AU - Miles, Timothy F.

AU - Spiess, Katja

AU - Jude, Kevin M.

AU - Tsutsumi, Naotaka

AU - Burg, John S.

AU - Ingram, Jessica R.

AU - Waghray, Deepa

AU - Hjorto, Gertrud M.

AU - Larsen, Olav

AU - Ploegh, Hidde L.

AU - Rosenkilde, Mette M.

AU - Garcia, K. Christopher

PY - 2018/6/8

Y1 - 2018/6/8

N2 - 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

AB - 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

U2 - 10.7554/eLife.35850

DO - 10.7554/eLife.35850

M3 - Journal article

C2 - 29882741

SN - 2050-084X

VL - 7

JO - eLife

JF - eLife

M1 - e35850

ER -