Structural basis for the constitutive activity and immunomodulatory properties of the Epstein-Barr virus-encoded G protein-coupled receptor BILF1
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Structural basis for the constitutive activity and immunomodulatory properties of the Epstein-Barr virus-encoded G protein-coupled receptor BILF1. / Tsutsumi, Naotaka; Qu, Qianhui; Mavri, Masa; Baggesen, Maibritt S.; Maeda, Shoji; Waghray, Deepa; Berg, Christian; Kobilka, Brian K.; Rosenkilde, Mette M.; Skiniotis, Georgios; Garcia, K. Christopher.
I: Immunity, Bind 54, Nr. 7, 2021, s. 1405-+.Publikation: Bidrag til tidsskrift › Tidsskriftartikel › Forskning › fagfællebedømt
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TY - JOUR
T1 - Structural basis for the constitutive activity and immunomodulatory properties of the Epstein-Barr virus-encoded G protein-coupled receptor BILF1
AU - Tsutsumi, Naotaka
AU - Qu, Qianhui
AU - Mavri, Masa
AU - Baggesen, Maibritt S.
AU - Maeda, Shoji
AU - Waghray, Deepa
AU - Berg, Christian
AU - Kobilka, Brian K.
AU - Rosenkilde, Mette M.
AU - Skiniotis, Georgios
AU - Garcia, K. Christopher
PY - 2021
Y1 - 2021
N2 - Epstein-Barr virus (EBV) encodes a G protein-coupled receptor (GPCR) termed BILF1 that is essential for EBV-mediated immunosuppression and oncogenesis. BILF1 couples with inhibitory G protein (Gi), the major intracellular signaling effector for human chemokine receptors, and exhibits constitutive signaling activity; the ligand(s) for BILF1 are unknown. We studied the origins of BILF1's constitutive activity through structure determination of BILF1 bound to the inhibitory G protein (Gi) heterotrimer. The 3.2-angstrom resolution cryo-electron microscopy structure revealed an extracellular loop within BILF1 that blocked the typical chemokine binding site, suggesting ligand-autonomous receptor activation. Rather, amino acid substitutions within BILF1 transmembrane regions at hallmark ligand-activated class A GPCR "microswitches'' stabilized a constitutively active BILF1 conformation for Gi coupling in a ligand-independent fashion. Thus, the constitutive activity of BILF1 promotes immunosuppression and virulence independent of ligand availability, with implications for the function of GPCRs encoded by related viruses and for therapeutic targeting of EBV.
AB - Epstein-Barr virus (EBV) encodes a G protein-coupled receptor (GPCR) termed BILF1 that is essential for EBV-mediated immunosuppression and oncogenesis. BILF1 couples with inhibitory G protein (Gi), the major intracellular signaling effector for human chemokine receptors, and exhibits constitutive signaling activity; the ligand(s) for BILF1 are unknown. We studied the origins of BILF1's constitutive activity through structure determination of BILF1 bound to the inhibitory G protein (Gi) heterotrimer. The 3.2-angstrom resolution cryo-electron microscopy structure revealed an extracellular loop within BILF1 that blocked the typical chemokine binding site, suggesting ligand-autonomous receptor activation. Rather, amino acid substitutions within BILF1 transmembrane regions at hallmark ligand-activated class A GPCR "microswitches'' stabilized a constitutively active BILF1 conformation for Gi coupling in a ligand-independent fashion. Thus, the constitutive activity of BILF1 promotes immunosuppression and virulence independent of ligand availability, with implications for the function of GPCRs encoded by related viruses and for therapeutic targeting of EBV.
KW - CLASS-I MOLECULES
KW - HIGH-LEVEL EXPRESSION
KW - LIGAND RECOGNITION
KW - BINDING-SITE
KW - CHEMOKINE
KW - IDENTIFICATION
KW - COMPLEX
KW - SYSTEM
KW - VISUALIZATION
KW - ACTIVATION
U2 - 10.1016/j.immuni.2021.06.001
DO - 10.1016/j.immuni.2021.06.001
M3 - Journal article
C2 - 34216564
VL - 54
SP - 1405-+
JO - Immunity
JF - Immunity
SN - 1074-7613
IS - 7
ER -
ID: 275059489