Structural characterization of anti-inflammatory immunoglobulin G Fc proteins

Copyright © 2014 Elsevier Ltd. All rights reserved..

Immunoglobulin G (IgG) is a central mediator of host defense due to its ability to recognize and eliminate pathogens. The recognition and effector responses are encoded on distinct regions of IgGs. The diversity of the antigen recognition Fab domains accounts for IgG's ability to bind with high specificity to essentially any antigen. Recent studies have indicated that the Fc effector domain also displays considerable heterogeneity, accounting for its complex effector functions of inflammation, modulation, and immune suppression. Therapeutic anti-tumor antibodies, for example, require the pro-inflammatory properties of the IgG Fc to eliminate tumor cells, while the anti-inflammatory activity of intravenous IgG requires specific Fc glycans for activity. In particular, the anti-inflammatory activity of intravenous IgG is ascribed to a small population of IgGs in which the Asn297-linked complex N-glycans attached to each Fc CH2 domain include terminal α2,6-linked sialic acids. We used chemoenzymatic glycoengineering to prepare fully disialylated IgG Fc and solved its crystal structure. Comparison of the structures of asialylated Fc, sialylated Fc, and F241A Fc, a mutant that displays increased glycan sialylation, suggests that increased conformational flexibility of the CH2 domain is associated with the switch from pro-inflammatory to anti-inflammatory activity of the Fc.

Medienart:

E-Artikel

Erscheinungsjahr:

2014

Erschienen:

2014

Enthalten in:

Zur Gesamtaufnahme - volume:426

Enthalten in:

Journal of molecular biology - 426(2014), 18 vom: 09. Sept., Seite 3166-3179

Sprache:

Englisch

Beteiligte Personen:

Ahmed, Alysia A [VerfasserIn]
Giddens, John [VerfasserIn]
Pincetic, Andrew [VerfasserIn]
Lomino, Joseph V [VerfasserIn]
Ravetch, Jeffrey V [VerfasserIn]
Wang, Lai-Xi [VerfasserIn]
Bjorkman, Pamela J [VerfasserIn]

Links:

Volltext

Themen:

Anti-Inflammatory Agents
Antigens
IVIG
Immunoglobulin Fc Fragments
Immunoglobulin G
Immunoglobulins, Intravenous
Inflammation
Journal Article
N-linked glycan
Polysaccharides
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Sialic Acids
Sialylated IgG Fc
X-ray crystallography

Anmerkungen:

Date Completed 29.12.2014

Date Revised 21.10.2021

published: Print-Electronic

PDB: 4Q6Y, 4Q74, 4Q7D

Citation Status MEDLINE

doi:

10.1016/j.jmb.2014.07.006

funding:

Förderinstitution / Projekttitel:

PPN (Katalog-ID):

NLM240177754