FcγRIIB-I232T polymorphic change allosterically suppresses ligand binding.
FcγRIIB
allosterically conformational change
human
immunology
in-situ 2D binding kinetics
inflammation
membrane receptor
molecular biophysics
single-nucleotide polymorphism
structural biology
systemic lupus erythematosus
Journal
eLife
ISSN: 2050-084X
Titre abrégé: Elife
Pays: England
ID NLM: 101579614
Informations de publication
Date de publication:
25 07 2019
25 07 2019
Historique:
received:
22
03
2019
accepted:
25
07
2019
pubmed:
26
7
2019
medline:
8
2
2020
entrez:
26
7
2019
Statut:
epublish
Résumé
FcγRIIB binding to its ligand suppresses immune cell activation. A single-nucleotide polymorphic (SNP) change, I232T, in the transmembrane (TM) domain of FcγRIIB loses its suppressive function, which is clinically associated with systemic lupus erythematosus (SLE). Previously, we reported that I232T tilts FcγRIIB's TM domain. In this study, combining with molecular dynamics simulations and single-cell FRET assay, we further reveal that such tilting by I232T unexpectedly bends the FcγRIIB's ectodomain toward plasma membrane to allosterically impede FcγRIIB's ligand association. I232T substitution reduces in situ two-dimensional binding affinities and association rates of FcγRIIB to interact with its ligands, IgG1, IgG2 and IgG3 by three to four folds. This allosteric regulation by an SNP provides an intrinsic molecular mechanism for the functional loss of FcγRIIB-I232T in SLE patients.
Identifiants
pubmed: 31343409
doi: 10.7554/eLife.46689
pii: 46689
pmc: PMC6711707
doi:
pii:
Substances chimiques
FCGR2B protein, human
0
Immunoglobulin G
0
Mutant Proteins
0
Receptors, IgG
0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Subventions
Organisme : National Basic Research Program of China
ID : 2015CB910800
Pays : International
Organisme : National Natural Science Foundation of China
ID : 31470900
Pays : International
Organisme : National Natural Science Foundation of China
ID : 31522021
Pays : International
Organisme : National Natural Science Foundation of China
ID : 11672317
Pays : International
Organisme : National Natural Science Foundation of China
ID : 11772348
Pays : International
Organisme : Fundamental Research Funds for the Central Universities
ID : 2015XZZX004-32
Pays : International
Organisme : Natural Basic Research Program of China
ID : 2015CB910800
Pays : International
Organisme : Natural Science Foundation of China
ID : 31470900
Pays : International
Organisme : Natural Science Foundation of China
ID : 31522021
Pays : International
Organisme : Natural Science Foundation of China
ID : 11672317
Pays : International
Organisme : Natural Science Foundation of China
ID : 11772348
Pays : International
Organisme : Fundamental Research Founds for the Central Universities
ID : 2015XZZX004-32
Pays : International
Informations de copyright
© 2019, Hu et al.
Déclaration de conflit d'intérêts
WH, YZ, XS, TZ, LX, HX, ZL, WL, JL, WC No competing interests declared
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