Blood, 15 June 2002, Vol. 99, No. 12, pp. 4649-4650
CORRESPONDENCE
To the editor:
Implication for how the single nucleotide polymorphism
(SNP) of Fc receptor, Fc
RIIIa alters the interaction
with anti-CD20 monoclonal antibody
We read a recent interesting article by Cartron et
al.1 The article indicated that the single nucleotide
polymorphism (SNP) of IgG Fc receptor Fc
RIIIa (FCGR3A)
molecule affects clinical outcome of anti-CD20 monoclonal antibody
therapy for follicular non-Hodgkin lymphoma.1 We created
homology models of variant FCGR3A molecules based on homology between
variant FCGR3A and known 3-dimensional structure of soluble
CD16.2 Each model was superimposed onto a 1:1 complex of
soluble CD16 and Fc fragment of human IgG1 (Figure
1A-B). These models indicate that the
position of variation 158Val/Phe exists at the F-G loop of the
molecules that serves as binding interface and is surrounded by both
chains of Fc fragments of IgG1 (Figure 1C). Since the side chain of Phe is hydrophobic and quite bigger than that of Val, the polymorphism can
affect the major conformation or the hydrophobicity of the surface of
the binding interface. These findings are compatible with previous
observations that suggested FCGR3A binding interface3,4 and
may help in understanding the way the SNP affects the binding with Fc
portion of human IgG1.
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| Figure 1.
Homology models of the Fc fragment of hIgG1.
The homology
model has been developed using 1e4k.pdb in Brookhaven Protein Data Bank
as a template.2 The modeling has been done with
SwissPdbViewer and the SwissProt modeling server. The raytracing of the
figure has been done using the program PovRay in SGI computer at Human
Genome Center, Institute of Medical Science, the University of Tokyo.
The models are superimposed onto 1e4k.pdb based on homology. Models are
shown in  -strand,  -helical presentation connected with -carbon
trace. The side chains of Val158 and Phe158 are shown in space filling
model. (A) Docking between FCGR3A-Val and hIgG1. (B) Docking between
FCGR3A-Phe and hIgG1. (C) Details of amino acid residues close to 158F
of FCGR3A-Phe molecules. The side chains of IgG1 molecule within 10Å
from 158 Phe are shown in balls and sticks model.
|
|
Yasuo Oshima and Akio Fujimura
Correspondence: Yasuo Oshima, Dept of Clinical Pharmacology,
Jichi Medical School, 3311 Yakushiji, Minamikawachimachi Kawachigun
3290298 Tochigiken, Japan; e-mail: oshima{at}jichi.ac.jp
References
1.
Cartron G, Dacheux L, Salles G, et al.
Therapeutic activity of humanized anti-CD20 monoclonal antibody and polymorphism in IgG Fc receptor FcRIIIa gene.
Blood.
2002;99:754-758[Abstract/Free Full Text].
2.
Sondermann P, Huber R, Oosthuizen V, Jacob U.
The 3.2-Å crystal structure of the human IgG1 Fc fragment-Fc RIII complex.
Nature.
2000;406:267-273[CrossRef][Medline]
[Order article via Infotrieve].
3.
Tamm A, Schmidt RE.
The binding epitopes of human CD16 (FcRIII) monoclonal antibodies. Implications for ligand binding.
J Immunol.
1996;157:1576-1581[Abstract].
4.
Tamm A, Kister A, Nolte KU, Gessner JE, Schmidt RE.
The IgG binding site of human FcRIIIB receptor involves CC' and FG loops of the membrane-proximal domain.
J Biol Chem.
1996;271:3659-3666[Abstract/Free Full Text].
Response:
Implication for how the single nucleotide polymorphism
(SNP) of Fc receptor FcRIIIa alters the interaction
with anti-CD20 monoclonal antibody
The 2 available crystal structures of the extracellular part of
CD16 in complex with IgG1 Fc1,2 are derived from the FcRIIIb receptor, which is a glycosyl-phosphatidyl-anchored
receptor expressed by neutrophils and eosinophils. However, due to 96% identity in the extracellular domains, it is assumed that the described
structures can be used as a template to model the FcRIIIa transmembrane receptor expressed by monocytes and natural killer (NK) cells. The FcRIIIb receptor has a valine residue at
position 158, like the FcRIIIa-158Val allotype. We agree with Oshima
and Fujimoro that a phenylalanine residue at position 158 of FcRIIIa could alter the binding of human IgG1 Fc, notably by modifying the
hydrophobic core involved in the binding to one of the CH2 domain of
the antibody. The model provided by Oshima and Fujimoro supports our
own results, and we thank them for this additional information.
Guillaume Cartron, Laurent Dacheux, Gilles Salles, Philippe Solal-Celigny, Pierre Bardos, Philippe Colombat, and Hervé Watier
Correspondence: Hervé Watier, Laboratoire d'Immunologie,
Faculté de Médecine, 2 bis boulevard Tonnellé, 37032 Tours cedex, France; e-mail: watier{at}med.univ-tours.fr
References
1.
Sondermann P, Huber R, Oosthuizen V, Jacob U.
The 3.2-Å crystal structure of the human IgG1 Fc fragment-Fc RIII complex.
Nature.
2000;406:267-273[CrossRef][Medline]
[Order article via Infotrieve].
2.
Radeav S, Motyka S, Fridman WH, Sautes-Fridman C, Sun PD.
The structure of a human type III Fc gamma receptor in complex with Fc.
J Biol Chem.
2001;276:16469-16477[Abstract/Free Full Text].
3.
Cartron G, Dacheux L, Salles G, et al.
Therapeutic activity of humanized anti-CD20 monoclonal antibody and polymorphism in IgG Fc receptor FcRIIIa gene.
Blood.
2002;99:754-758.
