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Identification of a New Cholesterol‐Binding Site within the IFN‐ γ Receptor that is Required for Signal Transduction
Author(s) -
Morana Ornella,
NietoGarai Jon Ander,
Björkholm Patrik,
Bernardino de la Serna Jorge,
Terrones Oihana,
Arboleya Aroa,
Ciceri Dalila,
RojoBartolomé Iratxe,
Blouin Cédric M.,
Lamaze Christophe,
Lorizate Maier,
Contreras FrancescXabier
Publication year - 2022
Publication title -
advanced science
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.388
H-Index - 100
ISSN - 2198-3844
DOI - 10.1002/advs.202105170
Subject(s) - signal transduction , transmembrane protein , microbiology and biotechnology , receptor , cell surface receptor , biology , transmembrane domain , chemistry , biochemistry
The cytokine interferon‐gamma (IFN‐ γ ) is a master regulator of innate and adaptive immunity involved in a broad array of human diseases that range from atherosclerosis to cancer. IFN‐ γ exerts it signaling action by binding to a specific cell surface receptor, the IFN‐ γ receptor (IFN‐ γ R), whose activation critically depends on its partition into lipid nanodomains. However, little is known about the impact of specific lipids on IFN‐ γ R signal transduction activity. Here, a new conserved cholesterol (chol) binding motif localized within its single transmembrane domain is identified. Through direct binding, chol drives the partition of IFN‐ γ R2 chains into plasma membrane lipid nanodomains, orchestrating IFN‐ γ R oligomerization and transmembrane signaling. Bioinformatics studies show that the signature sequence stands for a conserved chol‐binding motif presented in many mammalian membrane proteins. The discovery of chol as the molecular switch governing IFN‐ γ R transmembrane signaling represents a significant advance for understanding the mechanism of lipid selectivity by membrane proteins, but also for figuring out the role of lipids in modulating cell surface receptor function. Finally, this study suggests that inhibition of the chol‐IFN γ R2 interaction may represent a potential therapeutic strategy for various IFN‐ γ ‐dependent diseases.

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