Fc receptors constitute a group of membrane proteins that interact with IgG Fc regions. The three classes of human Fc receptors (FcRI, FcRII, FcRIII) belong to the Ig gene superfamily and are widely expressed in hematopoietic cell lineages (2, 3, 4, 5) . FcRI (CD64) binds IgG with high affinity, whereas FcRII (CD32) and FcRIII (CD16) are low affinity receptors, interacting predominantly with immune complexes of the IgG3 and IgG1 subclasses(6, 7) .

Human class III receptors are represented by two isoforms that differ in their membrane anchors(8) , expression patterns, and affinities to IgG. The transmembrane FcRIIIA (9) receptor is expressed on NK cells, macrophages, on subsets of monocytes, and T cells in association with dimers of the -chain of FcRI (10, 11, 12) and/or the -chain of T cell receptor(13) . Expression of the glycosylphosphatidylinositol-anchored FcRIIIB isoform is restricted to neutrophils(8, 14, 15, 16) . Tissue-specific expression of the two isoforms can be regulated at the transcriptional level(17, 18) . FcRIIIA binds IgG1 and IgG3 complexes with higher affinity (K 3 10M) than the B isoform (K 10M) and is able to interact with monomeric IgG(19, 20, 21) . FcRIIIB is represented by two allelic forms, NA1 and NA2, which can be detected with certain specific CD16 monoclonal antibodies(22, 23) . NA1 and NA2 (24) differ in their glycosylation patterns (25) and in their ability to trigger phagocytosis by neutrophils(26, 27) .

The Ig-binding extracellular regions of Fc receptors contain two (FcRII, FcRIII, FcRI) or three (FcRI) Ig-like disulfide-bonded domains (2, 3, 4, 5) composed of seven antiparallel -sheets(28) . Loops between the -sheets are likely to be involved in interactions with the ligands.

The membrane-proximal domain is crucial for IgG binding by most of the Fc receptors studied, i.e. human FcRII(1, 29, 30) , human FcRI(30, 31, 32) , mouse FcRII(33, 34) , and rat FcRI(31) . The membrane-distal domain of FcRIIIB, when fused to domains 3-5 of ICAM-1, did not react with IgG(35) . Thus, to identify the IgG binding sites of FcRIII, we focused on the second, membrane-proximal domain of FcRIIIB. We predicted potential -turn regions of the second Ig-like domain with the aid of the PC Gene program, and within these regions, amino acid residues were exchanged with the equivalent ones in the -chain of the human high affinity receptor for IgE, FcRI (36) . The resulting chimeric FcRIII/FcRI receptors should show diminished IgG binding affinity, since the extracellular part of FcRI reveals significant amino acid identity (41%) with FcRIIIB, but FcRI does not interact with IgG(30) .

Chimeric FcRIII/FcRI receptors revealed several regions on FcRIIIB (amino acids 125-127, 152-158, 160-163), substitution of which resulted in decreased interaction with IgG. Following single residue mutagenesis and molecular modeling of the receptor indicated that amino acids critical for ligand binding are apparently located on the loops connecting C and C` -sheets (Gln) as well as F and G -sheets (Lys, Val) and on the F -sheet (Arg) all on the second extracellular domain of FcRIIIB. These residues may constitute one discontinuous binding area on the GFC -sheet surface for the ligand, IgG1 or IgG3 complexes. This was further supported by the finding that the epitope for the IgG-binding inhibitory monoclonal antibody (mAb) ()3G8 (37) was localized on the same FG loop of the membrane-proximal domain.

MATERIALS AND METHODS

cDNAs and mAbs

Monoclonal antibodies to CD16 (3G8(37) , CLB-Fcgran1(38) , DJ130c, MEM-154, LNK16, and B88-9) were clustered and characterized in the Fifth International Workshop of Leukocyte Differentiation Antigens (22) . W6/32 (39) reacts with a monomorphic determinant of human HLA-A, B, and was used as a positive control.

IgG Complexes, Dimers, and IgE

Human myeloma cell line SKO-007 (41) secreting IgE was a gift from Dr. R. Lamers (Max Planck Institute for Immunobiology, Freiburg, Germany). The cells were cultured in Iscove's modified Eagle`s medium (Life Technologies, Inc., Eggenstein, Germany) supplemented with 1% fetal calf serum (PAA, Linz, Austria), 2 mML-glutamine, 100 units/ml penicillin, 100 µg/ml streptomycin (Biochrom KG, Berlin, Germany). IgE was purified from culture supernatants on a NHS-activated HiTrap column (Pharmacia) coupled with polyclonal antibody to hIgE (The Binding Site, Heidelberg, Germany).

Construction of Chimeric FcRIIIB/FcRI and Mutant FcRIIIB cDNAs

Chimeric FcRIIIA/B receptor was constructed by cloning the 536-bp SphI-HincII fragment coding for the extracellular part of the FcRIIIA gene into the FcRIIIB gene.

Cells and Transient Transfection

IgG Binding Assays and Flow Cytometry

Molecular Modeling of FcRIIIB

RESULTS AND DISCUSSION

Mapping of the Regions Involved in IgG Binding on the Membrane-proximal Domain of FcRIIIB

Figure 1: Alignment of the membrane-proximal domains of hFcRIIIB, hFcRI, and hFcRIIA. Locations of the regions of highest -turn probability in FcRIIIB predicted by the Chou and Fasman method are indicated as gray bars over the sequence. Chimeric FcRIIIB/FcRI receptors were designed based on this analysis. The amino acid residues exchanged between FcRIIIB and FcRI in the chimeras are boxed. Residues involved in ligand binding in FcRIIA are boxed on that sequence.

The wild-type and chimeric receptors were transiently expressed in 293 cells, and the structural integrity of the receptors was assessed with a panel of six CD16 mAbs (3G8, DJ130c, Gran1, MEM-154, LNK16, and B88-9). No significant differences between the interaction with wild-type FcRIIIB and five of the eight chimeras were observed with the mAbs (Table 1), indicating that the mutations had caused no major alterations in the structure of these chimeric receptors. In contrast, the chimera 160-163 was not recognized by the ligand-binding inhibitory mAb 3G8, and the binding with the mAbs Gran1, MEM-154, and B88-9 was affected (about 30-60% of wild-type receptor). mAb DJ130c reacted at the wild-type level with all the chimeras (Table 1). Recognition of two chimeric receptors, 113-118 and 134-138, was significantly decreased by most of the CD16 mAbs (Table 1). Thus, we assumed extensive structural alterations in the membrane-proximal domains of these receptors.

The epitopes for the mAbs used have not been extensively studied yet. DJ130c is considered to bind the membrane-distal domain of FcRIII (46) . This explains the reactivity of the antibody with all the chimeras. The other five mAbs used are directed against the membrane-proximal domain(46) . ()3G8 is known to interfere with the ligand binding of the receptor(37, 46) . Thus, the complete loss of binding with 3G8 indicates a major alteration within the IgG binding site on the chimera 160-163.

In binding assays of transfected 293 cells with hIgG1 complexes, a K of 53.1 nM was calculated for the wild-type FcRIIIB (Table 1). The affinity of the receptor to covalently linked highly purified hIgG1 dimers was about 10 times lower (K = 4.6 10M, Table 1), presumably due to the lower valency of the dimeric ligand.

A FcRIIIA/B chimera that maintained the extracellular domains of FcRIIIA in the glycosylphosphatidylinositol-anchored molecule revealed similar to wild-type FcRIIIB affinities to IgG1 complexes (K = 50.7 nM, Table 1and Fig. 2) as well as to dimers (K = 2.7 10M, Table 1). Hence, we suppose that the minor differences in the amino acid sequences of the extracellular domains of these two isoforms do not account for the higher IgG binding capacity of FcRIIIA(20) .

Figure 2: Binding of the chimeric receptors to hIgG1 complexes. Binding of serial dilutions of heat-aggregated hIgG1 to 293 cells transfected with cDNAs of wt FcRIIIB (, dashed line), chimeras FcRIIIA/B (, dashed line), 97-99 (), 125-127 (), 129-131 (&cjs3560;), 147-148 (*), 152-158 (), 160-163 (), and of mock cells (&cjs3649;, dashed line). The panel represents results of a typical experiment. Fraction of bound IgG1 was calculated according to the formula f = FL - FL/FL - FL, where FL = anti-IgG fluorescence of the given receptor at the provided concentration of IgG complexes, FL = anti-IgG fluorescence in the absence of IgG, and FL = anti-IgG fluorescence of the wt FcRIIIB at saturation. Binding assays were performed in triplicates.

293 cells bearing the chimeras 97-99, 129-131, and 147-148 showed binding affinities similar to wt FcRIIIB, (Fig. 2). In contrast, chimeras 125-127 and 152-158 bound hIgG1 complexes as well as dimers at significantly lower levels (K values for the chimeras are shown in Table 1). Chimera 160-163 had almost completely lost the capacity to bind IgG (Fig. 2). Since this chimera was still recognized by most of the CD16 mAbs except 3G8, we speculate that we have rather replaced residues functional in ligand and 3G8 binding than destroyed the overall structure of the second domain.

Binding affinities of the receptors to chemically cross-linked IgG dimers were lower than to- heat-aggregated complexes (Table 1). However, the chimeric receptors reacted with hIgG1 dimers and large complexes in the same manner, i.e. the chimeras 127-127, 152-158, and 160-163 revealed decreased binding capacities to both the ligands, whereas the other three chimeras (97-99, 129-131, and 147-148) showed binding affinities comparable to the wild-type FcRIIIB.

Chimeras 113-118 and 134-138 did not bind IgG as well as most of the CD16 mAbs mapped to react with the membrane-proximal domain. As discussed below, the loss of IgG binding was considered to result from the destroyed structure of the domain, and these chimeras were excluded from further mutational analysis.

None of the transfectants expressing chimeric receptors were able to interact with hIgE (data not shown). Evidently, the FcRI-derived amino acid residues in the chimeras are not directly involved in IgE binding or are not sufficient for the binding detectable in our assays.

Localization of the Putative IgG Binding Regions on the Molecular Model of the Membrane-proximal Domain of FcRIIIB

Figure 3: Molecular model of the membrane-proximal domain of FcRIIIB. Ribbon diagram presentation of a ``MOLSCRIPT'' (58) and ``RASTER three-dimensional'' (59) drawing showing the predicted -strands G, F, C in the front (light) and A, B, E in the back (dark). The regions that were replaced with the equivalent ones from the FcRI in the chimeric receptors are indicated. The cysteines that form the disulfide bond are shown on F and B -sheets.

Amino acids substituted in the chimeras that did not have any effect on ligand binding (97-99, 129-131, and 147-148) are positioned apart from the binding surface on this model. Residues 97-99 stretch between the two extracellular domains, and 147-148 are located on the E -sheet. Both the regions are located on the ABE surface of the membrane-proximal domain, thus on the opposite side of the potential binding area (Fig. 3). Residues 129-131 are placed on the CC` loop, opposite to the 125-127 region. Replacement of these amino acids seems not to affect the function of the neighboring putative binding residues 125-127, since the substitution did not influence the interaction with IgG (Table 1, Fig. 2).

The overall structure of two of the chimeric receptors (113-118 and 134-138) was considered to be disrupted according to the monoclonal antibody data. Location of the amino acids 134-138 on the C` -sheet that is presumably stabilizing the two -sheet surfaces would explain the disruption of the structure of the domain when these residues were substituted. According to the model, the region 113-118 within the BC loop is also connecting the two -sheet surfaces and, therefore, likely to be stabilizing the conformation of the domain. In addition, this region can be involved in generating the binding site due to the close proximity to the FG loop, the potential binding structure for IgG.

The GFCC" surface of the membrane-proximal domain of hFcRII has been reported to be crucial for IgG binding(1) . The key residues on hFcRIIA (Fig. 1) are shown to locate on the FG loop of the domain on a molecular model of this receptor(1) . The FG loop is also involved in ligand binding in mouse FcRII(32, 33) . These data support our hypothesis that the FG loop of the membrane-proximal domain is the main binding determinant in FcRIII, as was demonstrated by the loss of IgG binding capacity after substituting the residues 160-163 on the putative FG loop.

Arg/His influences the interaction of hFcRIIA with hIgG2(47, 48) . The low responsive FcRIIA isoform harbors histidine in this position and interacts with human IgG2 but not with mouse IgG1, whereas arginine in the position 131 in FcRIIA abolishes the binding to hIgG2. Arg/His is located on the C`E loop on the FcRIIA model(1) . In hFcRIII, His is corresponding to the His/Arg in hFcRIIA (Fig. 1) and is putatively positioned on the C` -sheet. Since hFcRIII does not bind IgG2 and, according to our model, the C` -sheet remains conformationally distant from the GFC surface, we suggest the residues on this -sheet are not directly involved in hIgG1 binding.

Detailed Structure Analysis of the Potential Binding Site

Within the region 125-127 (LQN-YKD), replacement of Leu with Tyr and of Gln with Lys resulted in lower IgG binding capacities (K = 182 and 116 nM for IgG complexes, respectively, Table 1, Fig. 4A), comparable to that of the responsive chimera (K = 150 nM). In contrast, changing Asn to Asp did not alter the binding affinity of the mutant receptor (Fig. 4A, Table 1). Interaction with IgG1 dimers followed the same pattern, i.e. mutants Leu and Gln harbored decreased ligand binding capacities as compared to the wild-type receptor. Analyzing the receptor model, we supposed that only Glu and not Leu is directly involved in binding. We assume that replacing the small polar side chain of leucine with that of aromatic tyrosine in the mutant Leu has led to immense structural changes in the CC` loop and, thus, to interrupted ligand binding.

Figure 4: Binding of the single residue mutant receptors to hIgG1 complexes. Representative IgG1 binding experiments of the mutant receptors are grouped according to the chimeras they originate from. Panel A, 293 cells were transfected with cDNAs of wt FcRIIIB (, dashed line), chimera 125-127 (), mutant receptors Leu (), Gln (), Asn (), and vector DNA (&cjs3649;, dashed line). Panel B, transfectants of wt FcRIIIB (), chimera 152-158 (), Phe (), Arg (), and Leu (). Panel C, transfectants of wt FcRIIIB (), chimera 160-163 (), Ser (), Lys (), Asn (), Val (&cjs3560;), and Ser (). Experiments were performed in triplicates, and fractions bound were calculated as described in Fig. 2.

A IgG binding site of FcRIIIB has been described by Hibbs et al.(35) who identified a continuous binding region on the CC` loop of the second domain, Gln-Tyr, by alanine-scanning mutagenesis. In contrast to these data, our mutational analysis revealed no linearly continuous binding sites. In our experiments, replacement of the sequence Lys-Asp-Arg with Glu-Ala-Leu from FcRI did not influence IgG binding. Only conversions of the polar Leu and Gln (Fig. 6) to aromatic Tyr or positively charged Lys, respectively, disrupted ligand-receptor interaction, whereas changing the charge of the adjacent side chain (NH group of Asn to negatively charged O of Asp) did not affect the interaction at all. We suppose that substitution of every amino acid to alanine by Hibbs et al.(35) affected the structure of the CC` loop and, hence, the binding capacity, even when the residues neighboring to functional ones were changed. Gly was also recognized to be involved in IgG binding in that study. Glycine with only one hydrogen atom as the side chain can adopt a wider range of main chain conformations than other residues (28) and should play an important role in maintaining the structure of the CC` loop. This might as well explain the absence of ligand binding by mutated Gly, also demonstrated in that study(35) .

Figure 6: Space-filling presentation of the ligand binding domain of FcRIIIB. Amino acid residues putatively involved in IgG binding are colored. The N (Leu) and C termini (Ile) of the domain are indicated by cyan. The computer model was generated based on the previously described structure of a IgG Fab fragment (44) .

We constructed three mutants (Phe, Arg, and Leu) in the second region, 152-158. Analyzing the molecular model, Ser was found to be placed apart from the other residues and excluded from further studies. Replacement of the positively charged Arg (Fig. 4B, Table 1) with polar Thr resulted in the decrease of receptor function, while exchanging the neighboring residues Phe with Tyr and Leu with Lys did not have significant effects on IgG binding. Substitution of only the Arg with Thr disrupted receptor-ligand interaction to a considerably higher extent than did the replacement of the longer region, 152-158 (Table 1, Fig. 4B). We assume that the single residue replacement destroyed also the possible -sheet structure and ablated IgG binding capacity of the receptor. In contrast, when the whole F -sheet was exchanged in the chimera 152-158, IgG binding was decreased, apparently, due to the missing of the residue of direct interaction with the ligand.

Based on the chimera 160-163, the amino acid Ser was converted to Gln, Lys to Leu, Asn to Asp, Val to Tyr, and Ser to Glu. Two of the substitutions, Lys to Leu and Val to Tyr, resulted in decreased ligand binding capacities of the respective receptors. The mutation of Val almost abolished the ability to bind IgG (Fig. 4C, Table 1). Both the mutants reacted weakly with the mAbs 3G8 and B88-9, indicating that Lys and Val are located also within the epitopes for these antibodies. The three other mutant receptors, Ser, Asn, and Ser, resembled the wild-type receptor (Fig. 4C, Table 1), although in every instance a substantial change in charge and/or configuration of the side chain was generated. We conclude that Lys and Val, which are located according to the molecular model on the FG loop, are crucial for IgG binding, either being involved in direct interactions with the ligand or determining the conformation of the FG loop.

Binding Epitope of the mAb 3G8

Figure 5: Binding of transfectants with mAb 3G8. 293 cells transfected with the cDNAs of wt FcRIIIB (, dashed line), mutant receptors Lys (), Val (), Gln (), Arg (), and vector DNA (&cjs3649;, dashed line) were incubated with serial dilutions of 3G8 (0.1-20 µg/ml). Bound mAb was detected with fluorescein isothiocyanate-labeled anti-mouse antibody by fluorescence-activated cell sorter analysis. Fractions of 3G8 bound were calculated as described in the legend for Fig. 2.

hFcRIII-IgG Interaction

On IgG1 and IgG3, the natural ligands for these receptors, the lower hinge region (amino acids 233-237) has been identified to constitute a binding pocket for all Fc receptors(49, 50, 51, 52) . The lower hinge regions are different in IgG2 and IgG4, which explains also the failure of these subclasses to interact with Fc receptors. Based on these data, we suppose that the same structural elements on the low affinity Fc receptors, e.g. FG loops, are interacting with the same binding site, the lower hinge region on the IgG molecules. Although the amino acid residues found to be involved in ligand binding in FcRIIIB are not conserved among Fc receptors (Fig. 1), we think that the FG loops of the membrane-proximal domains of different Fc receptors constitute similar binding structures for IgG, whereas different single residues are involved in direct interactions.

The extensive amino acid sequence homology between FcRI and Fc receptors suggests that a similar folding pattern might be adopted by these receptors, and the FG loops could be even more widely used as an interaction site with immunoglobulins.

A relatively higher affinity to IgG has been reported for the FcRIIIA receptor(19, 20) . The minor differences in the extracellular polypeptide sequences of the FcRIII A and B were shown not to be responsible for the improved binding capacity of the A isoform, since the chimera FcRIIIA/B harboring the extracellular part of the A isoform in the B gene bound hIgG1 complexes and dimers similarly to the FcRIIIB. An additional binding site for FcRIIIA has been proposed in the CH3 domain of IgG(53, 54, 55) . Binding curves obtained in our experiments do not refer to the existence of a second binding site on FcRIIIB. However, the possibility remains to be studied that on NK cells, which express FcRIIIA in association with the -chain of the FcRI, the receptor exposes different interaction characteristics with IgG and thus endures higher affinity to the ligand.

Understanding the molecular basis of the interactions between Fc receptors and immunoglobulins is of great importance, since the use of antibodies as therapeutical agents is increasing. The low affinity Fc receptors are also believed to play an important role in inducing antibody-mediated inflammation(56, 57) . Several chronic inflammatory diseases like rheumatoid arthritis and leukocytoclastic vasculitis are linked to constant presence of antigen-antibody complexes and continuous activation of effector cells expressing Fc receptors. Identification of the binding sites on the receptors may provide new possibilities for treatment of these diseases by blocking Fc receptor-IgG interaction.

FOOTNOTES

*

This work was supported by Deutsche Forschungsgemeinschaft Grant SFB 244/A09. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore by hereby marked ``advertisement'' in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

§

Current address: Dept. of Mathematics, Hill Center, Rutgers University, New Brunswick, NJ 08903.

¶

To whom correspondence should be addressed. Tel.: 49-511-532-6656; Fax: 49-511-532-9067.

()

The abbreviations used are: mAb, monoclonal antibody; wt, wild type; bp, base pair.

()

A. Tamm and R. E. Schmidt, manuscript in preparation.

ACKNOWLEDGEMENTS

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