S. Radaev et Pd. Sun, Recognition of IgG by Fc gamma receptor - The role of Fc glycosylation andthe binding of peptide inhibitors, J BIOL CHEM, 276(19), 2001, pp. 16478-16483
Recently determined crystal structures of the complex between immunoglobuli
n constant regions (Fc) and their Fc-respective receptors (FcR) have reveal
ed the detailed molecular interactions of this receptor-ligand pair. Of par
ticular interest is the contribution of a glycosylation at Asn(297) of the
C(H)2 domain of IgG to receptor recognition. The carbohydrate moieties are
found outside the receptor Fe interface in all receptor Fe complex structur
es. To understand the role of glycosylation in FcR recognition, the recepto
r affinities of a deglycosylated IgG1 and its Fc fragment were determined b
y 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 gamma RIII.
Structurally, the carbohydrates attached to Asn(297) fill the cavity betwe
en the C(H)2 domains of Fc functioning equivalently as a hydrophobic core.
This may stabilize a favorable lower hinge conformation for the receptor bi
nding, The structure of the complex also revealed the dominance of the lowe
r hinge region in receptor.Fc recognition, To evaluate the potential of des
igning small molecular ligands to inhibit the receptor function, four lower
hinge peptides were investigated for their ability to bind to the receptor
Fc gamma RIII, These peptides bind specifically to Fc gamma RIII with affi
nities 20- to 100-fold lower than IgG1 and are able to compete with Fc in r
eceptor binding. The results of peptide binding illustrate new ways of desi
gning therapeutic compounds to block Fc receptor activation.