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J. Biol. Chem., Vol. 276, Issue 19, 16478-16483, May 11, 2001
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From the Structural Biology Section, Laboratory of Immunogenetics,
NIAID, National Institutes of Health, Rockville, Maryland 20852
Recently determined crystal structures of the
complex between immunoglobulin constant regions (Fc) and their
Fc-respective receptors (FcR) have revealed the detailed molecular
interactions of this receptor-ligand pair. Of particular interest is
the contribution of a glycosylation at Asn297 of the
CH2 domain of IgG to receptor recognition. The carbohydrate moieties are found outside the receptor·Fc interface in all
receptor·Fc complex structures. To understand the role of
glycosylation in FcR recognition, the receptor affinities of a
deglycosylated IgG1 and its Fc fragment were determined by solution
binding studies using surface plasmon resonance. The removal of
carbohydrates resulted in a non-detectable receptor binding to the Fc
alone and a 15- to 20-fold reduction of the receptor binding to IgG1, suggesting that the carbohydrates are important in the function of the
Fc
Recognition of IgG by Fc
Receptor
THE ROLE OF Fc GLYCOSYLATION AND THE BINDING OF PEPTIDE
INHIBITORS*
RIII. Structurally, the carbohydrates attached to
Asn297 fill the cavity between the CH2 domains
of Fc functioning equivalently as a hydrophobic core. This may
stabilize a favorable lower hinge conformation for the receptor
binding. The structure of the complex also revealed the dominance of
the lower hinge region in receptor·Fc recognition. To evaluate the
potential of designing small molecular ligands to inhibit the receptor
function, four lower hinge peptides were investigated for their ability
to bind to the receptor FcRIII. These peptides bind specifically to
FcRIII with affinities 20- to 100-fold lower than IgG1 and are able
to compete with Fc in receptor binding. The results of peptide binding
illustrate new ways of designing therapeutic compounds to block Fc
receptor activation.
*
This work was supported by intramural funding of NIAID,
National Institutes of Health.The costs of publication of this
article were defrayed in part by the
payment of page charges. The article must therefore be hereby marked
"advertisement" in
accordance with 18 U.S.C. Section
1734 solely to indicate this fact.
To whom correspondence should be addressed: the Structural Biology
Section, Laboratory of Immunogenetics, NIAID, National Institutes of
Health, 12441 Parklawn Dr., Rockville, MD 20852. Tel.: 301-496-3230;
Fax: 301-402-0284; E-mail: psun@nih.gov.
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