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T B Mcfadden - One of the best experts on this subject based on the ideXlab platform.
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regulation of the Immunoglobulin G1 receptor effect of prolactin on in vivo expression of the bovine mammary Immunoglobulin G1 receptor
Journal of Endocrinology, 1999Co-Authors: George M Barrington, Thomas E. Besser, William C Davis, J J Reeves, T B Mcfadden, R M AkersAbstract:Induction of colostrogenesis in non-pregnant cows was used to evaluate the relationship between prolactin (PRL) and mammary Immunoglobulin G1 (IgG1) receptor expression. Six of eleven non-pregnant, non-lactating Holstein cattle responded to a standard lactation induction protocol by development of elevated IgG1 concentrations in mammary secretions. In order to increase the diversity in PRL concentrations, two of the six cattle were treated with bromocriptine, and two others were treated with recombinant bovine PRL. Serum alpha-lactalbumin, serum PRL and mammary secretion IgG1 concentrations were measured throughout the experiment. Biopsies of mammary tissue were collected after induction of lactation, and after treatments to alter serum PRL. Immunohistochemistry was used to evaluate IgG1 receptor expression. Administration of recombinant bovine (rbPRL) was associated with increased lactogenic activity, decreased secretion IgG1 concentrations, and decreased IgG1 receptor expression. Decreased serum PRL, due to bromocriptine, was associated with decreased lactogenic activity and maintenance of IgG1 receptor expression. Results of this experiment are consistent with an effect of PRL in decreasing the expression of the bovine mammary IgG1 receptor at the onset of lactogenesis.
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effect of prolactin on in vitro expression of the bovine mammary Immunoglobulin G1 receptor
Journal of Dairy Science, 1997Co-Authors: George M Barrington, T E Besser, William C Davis, J J Reeves, T B McfaddenAbstract:Abstract Explants of mammary tissue from cows in late pregnancy were incubated for 72h in serum-free, hormonally defined media to investigate the regulation of the bovine mammary IgG 1 receptor. Treatments included incubation in basal medium alone, basal medium plus estradiol-17 β , basal medium plus prolactin, or basal medium plus estradiol-17 β and prolactin. α-Lactalbumin production was measured by radioimmunoassay in culture supernatants collected at 24, 48, and 72h. Explants were examined immunohistochemically for expression of the IgG 1 receptor at 24, 48, and 72h. α-Lactalbumin concentrations increased, and IgG 1 receptor expression decreased, by 72h with explants cultured in the medium containing prolactin. Results suggest that, in addition to its positive lactogenic effect, prolactin decreases expression of the bovine mammary IgG 1 receptor.
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expression of Immunoglobulin G1 receptors by bovine mammary epithelial cells and mammary leukocytes
Journal of Dairy Science, 1997Co-Authors: George M Barrington, T E Besser, William C Davis, J J Reeves, T B McfaddenAbstract:The objective of this study was to identify and evaluate expression of IgG1 receptors by different cell types in mammary tissue sections and digest-dispersed cells from the bovine mammary gland. An immunohistochemical system utilizing avidin-biotin-peroxidase complex demonstrated epithelial expression of IgG1 receptors in mammary tissue sections from cows producing colostrum but not from cows in lactation. Fluorescence flow cytometry demonstrated that cells dispersed in digests from both tissues producing colostrum and lactating tissues selectively bound IgG1. Fluorescence flow cytometry, using monoclonal antibodies to cell surface molecules, cytokeratin, and IgG1, revealed that leukocytes constituted the largest percentage of cells and were the predominant cell type binding IgG1 in mammary tissue digests. Although IgG1 binding to epithelial cells predominated in the gland during colostrum production in situ, digestion and filtration to produce single cell suspensions resulted in the loss of large numbers of epithelial cells. Studies of Ig binding of cells produced by enzymatic digestion must account for the types of cells surviving the digestion process.
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effect of prolactin on in vitro expression of the bovine mammary Immunoglobulin G1 receptor
Journal of Dairy Science, 1997Co-Authors: George M Barrington, Thomas E. Besser, William C Davis, J J Reeves, T B McfaddenAbstract:Explants of mammary tissue from cows in late pregnancy were incubated for 72 h in serum-free, hormonally defined media to investigate the regulation of the bovine mammary IgG1 receptor. Treatments included incubation in basal medium alone, basal medium plus estradiol-17 beta, basal medium plus prolactin, or basal medium plus estradiol-17 beta and prolactin. alpha-Lactalbumin production was measured by radioimmunoassay in culture supernatants collected at 24, 48, and 72 h. Explants were examined immunohistochemically for expression of the IgG1 receptor at 24, 48, and 72 h. alpha-Lactalbumin concentrations increased, and IgG1 receptor expression decreased, by 72 h with explants cultured in the medium containing prolactin. Results suggest that, in addition to its positive lactogenic effect, prolactin decreases expression of the bovine mammary IgG1 receptor.
Dennis R. Burton - One of the best experts on this subject based on the ideXlab platform.
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human recombinant antimannan Immunoglobulin G1 antibody confers resistance to hematogenously disseminated candidiasis in mice
Infection and Immunity, 2006Co-Authors: Mason X. Zhang, Carol Itatani, S C St Jeor, Charlotte M Bohlman, Paul W H I Parren, Dennis R. Burton, Thomas R KozelAbstract:Mannan is a major cell wall component found in Candida species. Natural antimannan antibody is present in sera from most normal adults, but its role in host resistance to hematogenously disseminated candidiasis is unknown. The purpose of this study was to develop recombinant human antimannan antibody and to study its protective function. A phage Fab display combinatorial library containing Fab genes from bone marrow lymphocytes was screened with Candida albicans yeast cells and chemically purified mannan. One antimannan Fab, termed M1, was converted to a full-length Immunoglobulin G1 antibody, M1G1, and M1G1 was produced in CHO cells. The M1G1 epitope was found in C. albicans serotypes A and B, Candida tropicalis, Candida guilliermondii, Candida glabrata, and Candida parapsilosis. Its expression was active at both 23°C and 37°C and uniform over the cell surface. BALB/c mice passively immunized with M1G1 were more resistant than control mice to a lethal hematogenous infection by C. albicans, as evidenced by extension of survival in an M1G1 dose-dependent manner (P, 0.08 to <0.001) and by reduction in number of infection foci and their size in the kidney. In vitro studies found that M1G1 promoted phagocytosis and phagocytic killing of C. albicans yeast cells by mouse peritoneal macrophages and was required for activation of the mouse complement cascade. Thus, human antimannan antibody may have a protective role in host resistance to systemic candidiasis.
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a novel human antibody against human immunodeficiency virus type 1 gp120 is v1 v2 and v3 loop dependent and helps delimit the epitope of the broadly neutralizing antibody Immunoglobulin G1 b12
Journal of Virology, 2003Co-Authors: Michael B Zwick, Paul W H I Parren, Min Wang, Robert Kelleher, Richard Jensen, Aran F Labrijn, Gerald V Quinnan, Dennis R. BurtonAbstract:The V1/V2 and V3 loops are proximal to the CD4 binding site (CD4bs) of human immunodeficiency virus type 1 (HIV-1) gp120 and undergo conformational change upon CD4 receptor engagement by the HIV-1 envelope spike. Nearly all of the reported monoclonal antibodies (MAbs) against the CD4bs exhibit a very limited capacity to neutralize HIV-1. However, one such human MAb, Immunoglobulin G1 (IgG1) b12, is uniquely able to neutralize primary isolates across subtypes with considerable potency. The molecular basis for the anti-HIV-1 activity of b12 is not fully understood but is relevant to vaccine design. Here we describe a novel human MAb, 4KG5, whose binding to monomeric gp120 is moderately enhanced by IgG1 b12. In sharp contrast, 4KG5 binding to gp120 is inhibited by soluble CD4 (sCD4) and by all other (n = 14) anti-CD4bs MAbs tested. 4KG5 is unable to recognize gp120 in which either V1, V2, or V3 has been deleted, and MAbs against the V2 or V3 loops inhibit the binding of 4KG5 to gp120. Moreover, 4KG5 is able to inhibit the binding of the CD4-induced MAbs 17b and X5 in the absence of sCD4, whereas 17b and X5 only weakly inhibit the binding of 4KG5 to gp120. Mutagenesis of gp120 provides further evidence of a discontinuous epitope of 4KG5 that is formed by the V1/V2 loop, the V3 loop, and a portion of the bridging sheet (C4). 4KG5 was isolated as a single-chain Fv from a phage display library constructed from the bone marrow of an HIV-1-seropositive subject (FDA2) whose serum neutralizes HIV-1 across subtypes. Despite its source, we observed no significant neutralization with 4KG5 against the autologous (R2) virus and several other strains of HIV-1. The results suggest a model in which antibody access to the CD4bs on the envelope spike of HIV-1 is restricted by the orientation and/or dynamics of the V1/V2 and V3 loops, and b12 avoids these restrictions.
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molecular features of the broadly neutralizing Immunoglobulin G1 b12 required for recognition of human immunodeficiency virus type 1 gp120
Journal of Virology, 2003Co-Authors: Michael B Zwick, Paul W H I Parren, Erica Ollmann Saphire, Sarah E Church, Min Wang, Jamie K Scott, Philip E Dawson, Ian A Wilson, Dennis R. BurtonAbstract:IgG1 b12 is a broadly neutralizing antibody against human immunodeficiency virus type 1 (HIV-1). The epitope recognized by b12 overlaps the CD4 receptor-binding site (CD4bs) on gp120 and has been a target for vaccine design. Determination of the three-dimensional structure of Immunoglobulin G1 (IgG1) b12 allowed modeling of the b12-gp120 interaction in which the protruding third complementarity-determining region (CDR) of the heavy chain (H3) was crucial for antibody binding. In the present study, extensive mutational analysis of the antigen-binding site of Fab b12 was carried out to investigate the validity of the model and to identify residues important for gp120 recognition and, by inference, key to the anti-HIV-1 activity of IgG1 b12. In all, 50 mutations were tested: 40 in H3, 4 each in H2 and L1, and 2 in L3. The results suggest that the interaction of gp120 with H3 of b12 is crucially dependent not only on a Trp residue at the apex of the H3 loop but also on a number of residues at the base of the loop. The arrangement of these residues, including aromatic side chains and side chains that hydrogen bond across the base of the loop, may rigidify H3 for penetration of the recessed CD4-binding cavity. The results further emphasize the importance to gp120 binding of a Tyr residue at the apex of the H2 loop that forms a second finger-like structure and a number of Arg residues in L1 that form a positively charged, shelf-like structure. In general, the data are consistent with the b12-gp120 interaction model previously proposed. At the gene level, somatic mutation is seen to be crucial for the generation of many of the structural features described. The Fab b12 mutants were also tested against the b12 epitope-mimic peptide B2.1, and the reactivity profile had many similarities but also significant differences from that observed for gp120. The paratope map of b12 may facilitate the design of molecules that are able to elicit b12-like activities.
George M Barrington - One of the best experts on this subject based on the ideXlab platform.
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regulation of the Immunoglobulin G1 receptor effect of prolactin on in vivo expression of the bovine mammary Immunoglobulin G1 receptor
Journal of Endocrinology, 1999Co-Authors: George M Barrington, Thomas E. Besser, William C Davis, J J Reeves, T B Mcfadden, R M AkersAbstract:Induction of colostrogenesis in non-pregnant cows was used to evaluate the relationship between prolactin (PRL) and mammary Immunoglobulin G1 (IgG1) receptor expression. Six of eleven non-pregnant, non-lactating Holstein cattle responded to a standard lactation induction protocol by development of elevated IgG1 concentrations in mammary secretions. In order to increase the diversity in PRL concentrations, two of the six cattle were treated with bromocriptine, and two others were treated with recombinant bovine PRL. Serum alpha-lactalbumin, serum PRL and mammary secretion IgG1 concentrations were measured throughout the experiment. Biopsies of mammary tissue were collected after induction of lactation, and after treatments to alter serum PRL. Immunohistochemistry was used to evaluate IgG1 receptor expression. Administration of recombinant bovine (rbPRL) was associated with increased lactogenic activity, decreased secretion IgG1 concentrations, and decreased IgG1 receptor expression. Decreased serum PRL, due to bromocriptine, was associated with decreased lactogenic activity and maintenance of IgG1 receptor expression. Results of this experiment are consistent with an effect of PRL in decreasing the expression of the bovine mammary IgG1 receptor at the onset of lactogenesis.
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effect of prolactin on in vitro expression of the bovine mammary Immunoglobulin G1 receptor
Journal of Dairy Science, 1997Co-Authors: George M Barrington, T E Besser, William C Davis, J J Reeves, T B McfaddenAbstract:Abstract Explants of mammary tissue from cows in late pregnancy were incubated for 72h in serum-free, hormonally defined media to investigate the regulation of the bovine mammary IgG 1 receptor. Treatments included incubation in basal medium alone, basal medium plus estradiol-17 β , basal medium plus prolactin, or basal medium plus estradiol-17 β and prolactin. α-Lactalbumin production was measured by radioimmunoassay in culture supernatants collected at 24, 48, and 72h. Explants were examined immunohistochemically for expression of the IgG 1 receptor at 24, 48, and 72h. α-Lactalbumin concentrations increased, and IgG 1 receptor expression decreased, by 72h with explants cultured in the medium containing prolactin. Results suggest that, in addition to its positive lactogenic effect, prolactin decreases expression of the bovine mammary IgG 1 receptor.
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expression of Immunoglobulin G1 receptors by bovine mammary epithelial cells and mammary leukocytes
Journal of Dairy Science, 1997Co-Authors: George M Barrington, T E Besser, William C Davis, J J Reeves, T B McfaddenAbstract:The objective of this study was to identify and evaluate expression of IgG1 receptors by different cell types in mammary tissue sections and digest-dispersed cells from the bovine mammary gland. An immunohistochemical system utilizing avidin-biotin-peroxidase complex demonstrated epithelial expression of IgG1 receptors in mammary tissue sections from cows producing colostrum but not from cows in lactation. Fluorescence flow cytometry demonstrated that cells dispersed in digests from both tissues producing colostrum and lactating tissues selectively bound IgG1. Fluorescence flow cytometry, using monoclonal antibodies to cell surface molecules, cytokeratin, and IgG1, revealed that leukocytes constituted the largest percentage of cells and were the predominant cell type binding IgG1 in mammary tissue digests. Although IgG1 binding to epithelial cells predominated in the gland during colostrum production in situ, digestion and filtration to produce single cell suspensions resulted in the loss of large numbers of epithelial cells. Studies of Ig binding of cells produced by enzymatic digestion must account for the types of cells surviving the digestion process.
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effect of prolactin on in vitro expression of the bovine mammary Immunoglobulin G1 receptor
Journal of Dairy Science, 1997Co-Authors: George M Barrington, Thomas E. Besser, William C Davis, J J Reeves, T B McfaddenAbstract:Explants of mammary tissue from cows in late pregnancy were incubated for 72 h in serum-free, hormonally defined media to investigate the regulation of the bovine mammary IgG1 receptor. Treatments included incubation in basal medium alone, basal medium plus estradiol-17 beta, basal medium plus prolactin, or basal medium plus estradiol-17 beta and prolactin. alpha-Lactalbumin production was measured by radioimmunoassay in culture supernatants collected at 24, 48, and 72 h. Explants were examined immunohistochemically for expression of the IgG1 receptor at 24, 48, and 72 h. alpha-Lactalbumin concentrations increased, and IgG1 receptor expression decreased, by 72 h with explants cultured in the medium containing prolactin. Results suggest that, in addition to its positive lactogenic effect, prolactin decreases expression of the bovine mammary IgG1 receptor.
Christian Lanshoeft - One of the best experts on this subject based on the ideXlab platform.
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generic hybrid ligand binding assay liquid chromatography high resolution mass spectrometry based workflow for multiplexed human Immunoglobulin G1 quantification at the intact protein level application to preclinical pharmacokinetic studies
Analytical Chemistry, 2017Co-Authors: Christian Lanshoeft, Sarah Cianferani, Olivier HeudiAbstract:The quantitative analysis of human Immunoglobulin G1 (hIgG1) by mass spectrometry is commonly performed using surrogate peptides after enzymatic digestion. Since some limitations are associated with this approach, a novel workflow is presented by hybridizing ligand binding assay (LBA) with liquid chromatography–high-resolution mass spectrometry (LC–HRMS) for hIgG1 quantification directly at the intact protein level. Different hIgG1s, including a [13C]-labeled version used as internal standard, were immuno-enriched from rat serum with a fully automated platform based on streptavidin coated tips and a biotinylated mouse anti-hIgG capture antibody targeting the fragment crystallizable region followed by overnight deglycosylation prior to LC–HRMS analysis. The proposed quantitative workflow utilized extracted ion chromatograms (XICs) from the nondeconvoluted full-scan MS spectrum. The assay was validated in terms of selectivity, sensitivity, accuracy/precision, carry-over, dilution linearity, and reproducibil...
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smart digest compared with pellet digestion for analysis of human Immunoglobulin G1 in rat serum by liquid chromatography tandem mass spectrometry
Analytical Biochemistry, 2016Co-Authors: Christian Lanshoeft, Olivier Heudi, Sarah CianferaniAbstract:The newly developed SMART Digest™ kit was applied for the sample preparation of human Immunoglobulin G1 (hIgG1) in rat serum prior to qualitative and quantitative analyses by liquid chromatography tandem mass spectrometry (LC-MS/MS). The sequence coverages obtained for the light and heavy chains of hIgG1A were 50 and 76%, respectively. The calibration curve was linear from 1.00 to 1000 μg/ml for three of four generic peptides. Overall, the SMART Digest™ kit resulted in similar quantitative data (linearity, sensitivity, accuracy, and precision) compared with the pellet digestion protocol. However, the SMART Digest™ required only 2 h of sample preparation with fewer reagents.
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the use of generic surrogate peptides for the quantitative analysis of human Immunoglobulin G1 in pre clinical species with high resolution mass spectrometry
Analytical and Bioanalytical Chemistry, 2016Co-Authors: Christian Lanshoeft, Sarah Cianferani, Olivier Heudi, Thierry Wolf, Samuel Barteau, Markus Walles, Franck Picard, Olivier KretzAbstract:In the present study, the application of a liquid chromatography high-resolution mass spectrometry (LC-HRMS) analytical assay for the quantitative analysis of a recombinant human Immunoglobulin G1 (hIgG1) in rat serum is reported using three generic peptides GPSVFPLAPSSK (GPS), TTPPVLDSDGSFFLYSK (TTP), and VVSVLTVLHQDWLNGK (VVS). Moreover, the deamidation site of a fourth peptide FNWYVDGVEVHNAK (FNW) was identified and further excluded from the assay evaluation due to the inaccuracy of the quantitative results. The rat serum samples were spiked with a fully labeled hIgG1 as internal standard (ISTD). The digestion with trypsin was performed onto the pellet prior to peptide analysis by LC-HRMS using a quadrupole time of flight (QTOF) mass analyzer operating in selected reaction monitoring (SRM) mode with enhanced duty cycles (EDC). The assay linearity for the three investigated peptides was established for a hIgG1 (hIgG1A) from 1.00 to 1000 μg mL(-1) with a mean coefficient of determination (R (2)) higher than 0.9868. The inter-day accuracy and precision obtained in rat serum over 3 days were ≤11.4 and ≤10.5%, respectively. Short-term stability on the auto-sampler at 6 °C for 30 h, at RT for 48 h, and a 100-fold dilution factor were demonstrated. In addition, QC samples prepared in cynomolgus monkey serum and measured with the present method met the acceptance criteria of ±20.0 and ≤20.0% for all three peptides regarding accuracy and precision, respectively. The LC-HRMS method was applied to the analysis of samples from five individual cynomolgus monkeys dosed with a second hIgG1 (hIgG1B) and consistent data were obtained compared to the LC-MS/MS method (conventional triple quadrupole (QqQ) mass analyzer operating in SRM). The present data demonstrate that LC-HRMS can be used for the quantitative analysis of hIgG1 in both species and that quantification is not only limited to classical QqQ instruments.
Adam W Barb - One of the best experts on this subject based on the ideXlab platform.
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the Immunoglobulin G1 n glycan composition affects binding to each low affinity fc γ receptor
mAbs, 2016Co-Authors: Ganesh P Subedi, Adam W BarbAbstract:ABSTRACTImmunoglobulin G1 (IgG1) is the most abundant circulating human antibody and also the scaffold for many therapeutic monoclonal antibodies (mAbs). The destruction of IgG-coated targets by cell-mediated pathways begins with an interaction between the IgG Fc region and multiple varieties of membrane-bound Fc γ receptors (FcγRs) on the surface of leukocytes. This interaction requires the presence of an asparagine-linked (N-)glycan on the Fc, and variations in the N-glycan composition can affect the affinity of CD16A binding (an FcγR). Contemporary efforts to glycoengineer mAbs focus on increasing CD16A affinity, and thus treatment efficacy, but it is unclear how these changes affect affinity for the other FcγRs. Here, we measure binding of the extracellular Fc-binding domains for human CD16A and B, CD32A, B and C, and CD64 to 6 well-defined IgG1 Fc glycoforms that cover ∼85% of the pool of human IgG1 Fc glycoforms. Core α1–6 fucosylation showed the greatest changes with CD16B (8.5-fold decrease), CD16...
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intramolecular n glycan polypeptide interactions observed at multiple n glycan remodeling steps through 13c 15n n acetylglucosamine labeling of Immunoglobulin G1
Biochemistry, 2015Co-Authors: Adam W BarbAbstract:Asparagine-linked (N) glycosylation is a common eukaryotic protein modification that affects protein folding, function, and stability through intramolecular interactions between N-glycan and polypeptide residues. Attempts to characterize the structure–activity relationship of each N-glycan are hindered by inherent properties of the glycoprotein, including glycan conformational and compositional heterogeneity. These limitations can be addressed by using a combination of nuclear magnetic resonance techniques following enzymatic glycan remodeling to simultaneously generate homogeneous glycoforms. However, widely applicable methods do not yet exist. To address this technological gap, immature glycoforms of the Immunoglobulin G1 fragment crystallizable (Fc) were isolated in a homogeneous state and enzymatically remodeled with [13C,15N]-N-acetylglucosamine (GlcNAc). UDP-[13C,15N]GlcNAc was synthesized enzymatically in a one-pot reaction from [13C]glucose and [15N-amido]glutamine. Modifying Fc with recombinantly...
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Restricted Motion of the Conserved Immunoglobulin G1 N-Glycan Is Essential for Efficient FcγRIIIa Binding
Structure, 2014Co-Authors: Ganesh P Subedi, Quinlin M. Hanson, Adam W BarbAbstract:Summary Immunoglobulin G1 (IgG1)-based therapies are widespread, and many function through interactions with low-affinity Fc γ receptors (FcγR). N-glycosylation of the IgG1 Fc domain is required for FcγR binding, though it is unclear why. Structures of the FcγR:Fc complex fail to explain this because the FcγR polypeptide does not bind the N-glycan. Here we identify a link between motion of the N-glycan and Fc:FcγRIIIa affinity that explains the N-glycan requirement. Fc F241 and F243 mutations decreased the N-glycan/polypeptide interaction and increased N-glycan mobility. The affinity of the Fc mutants for FcγRIIIa was directly proportional to the degree of glycan restriction (R 2 = 0.82). The IgG1 Fc K246F mutation stabilized the N-glycan and enhanced affinity for FcγRIIIa. Allosteric modulation of a protein/protein interaction represents a previously undescribed role for N-glycans in biology. Conserved features suggesting a similar N-glycan/aromatic interaction were also found in IgD, IgE, and IgM, but not IgA.
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Immunoglobulin G1 fc domain motions implications for fc engineering
Journal of Molecular Biology, 2014Co-Authors: Martin Frank, Ross C Walker, W N Lanzilotta, James H Prestegard, Adam W BarbAbstract:Abstract The fragment crystallizable (Fc) region links the key pathogen identification and destruction properties of Immunoglobulin G (IgG). Pathogen opsonization positions Fcs to activate pro-inflammatory Fcγ receptors (FcγRs) on immune cells. The cellular response and committal to a damaging, though protective, immune response are tightly controlled at multiple levels. Control mechanisms are diverse and in many cases unclear, but one frequently suggested contribution originates in FcγR affinity being modulated through shifts in Fc conformational sampling. Here, we report a previously unseen IgG1 Fc conformation. This observation motivated an extensive molecular dynamics investigation of polypeptide and glycan motions that revealed greater amplitude of motion for the N-terminal Cγ2 domains and N-glycan than previously observed. Residues in the Cγ2/Cγ3 interface and disulfide-bonded hinge were identified as influencing the Cγ2 motion. Our results are consistent with a model of Fc that is structurally dynamic. Conformational states that are competent to bind immune-stimulating FcγRs interconverted with Fc conformations distinct from those observed in FcγR complexes, which may represent a transient, nonbinding population.
