Structural basis of the interaction between IgG and fcγ receptors

Kato, Koichi; Fridman, Wolf‐Herman; Yamada, Wakako; Kobayashi, Kaoru; Uchiyama, Susumu; Kim, HaHyung; Enokizono, Junichi; Galinha, Annie; Kobayashi, Yuji; Fridman, Wolf Herman; Arata, Yoji; Shimada, Ichio

doi:10.1006/jmbi.1999.3351

Cited by 74 publications

(55 citation statements)

References 48 publications

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“…Concentration gradients for mixed solution under different concentration conditions are also best fit with ideal single component model ( Fig. S3B and C), although association-dissociation model was also assessed for the nonlinear fitting as our previous studies (18,19). The molecular weight determined from the nonlinear fitting is 41,300.…”

Section: Resultsmentioning

confidence: 82%

“…All NMR spectra were acquired at 303 K using Avance600 (Bruker BioSpin) and ECA920 (JEOL) spectrometers. Although the backbone resonances of MCFD2 have been deposited in the Biological Magnetic Resonance Bank under accession code BMRB-15789 (18), these data were collected at a different buffer condition from this report. Therefore, we assigned the backbone resonances of MCFD2 as well.…”

Section: Methodsmentioning

confidence: 99%

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Structural basis for the cooperative interplay between the two causative gene products of combined factor V and factor VIII deficiency

Nishio

Kamiya

Mizushima

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

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Combined deficiency of coagulation factors V and VIII (F5F8D), an autosomal recessive disorder characterized by coordinate reduction in the plasma levels of factor V (FV) and factor VIII (FVIII), is genetically linked to mutations in the transmembrane lectin ERGIC-53 and the soluble calcium-binding protein MCFD2. Growing evidence indicates that these two proteins form a complex recycling between the endoplasmic reticulum (ER) and the ER-Golgi intermediate compartment and thereby function as a cargo receptor in the early secretory pathway of FV and FVIII. For better understanding of the mechanisms underlying the functional coordination of ERGIC-53 and MCFD2, we herein characterize their interaction by x-ray crystallographic analysis in conjunction with NMR and ultracentrifugation analyses. Inspection of the combined data reveals that ERGIC-53-CRD binds MCFD2 through its molecular surface remote from the sugar-binding site, giving rise to a 1∶1 complex in solution. The interaction is independent of sugarbinding of ERGIC-53 and involves most of the missense mutation sites of MCFD2 so far reported in F5F8D. Comparison with the previously reported uncomplexed structure of each protein indicates that MCFD2 but not ERGIC-53-CRD undergoes significant conformational alterations upon complex formation. Our findings provide a structural basis for the cooperative interplay between ERGIC-53 and MCFD2 in capturing FV and FVIII.MCFD2 | ERGIC-53 | calcium-binding protein | cargo receptor | intracellular lectin C ombined deficiency of coagulation factors V and VIII (F5F8D) is an autosomal recessive disorder characterized by coordinate reduction in the plasma levels of factor V (FV) and factor VIII (FVIII) (1, 2) Extensive genetic analysis of F5F8D patients identified two genes that are associated with this disorder. Genetic mutations in LMAN1 account for approximately 70% of F5F8D families, whereas the remaining 30% families possess mutation in MCFD2 (3, 4). LMAN1 encodes the transmembrane lectin ERGIC-53 (ER-Golgi intermediate compound protein of 53 kDa) (5), which possesses a luminal carbohydrate recognition domain (CRD) with specificity for highmannose-type oligosaccharides (6, 7) and forms dimers or hexamers stabilized by disulfide bonds formed in its stalk domain (5, 8). By contrast, the product of MCFD2 is a soluble luminal protein with two EF-hand Ca 2þ -binding motifs (9). It has been shown that MCFD2 interacts with the CRD of ERGIC-53 in a Ca 2þ -dependent manner (9-11). Accumulating evidence indicates that this complex recycles between the endoplasmic reticulum (ER) and the ER-Golgi intermediate compartment (ERGIC) and thereby functions as a cargo receptor in the early secretory pathway of FV and FVIII (12).To gain a better understanding of the molecular mechanisms underlying the sorting and trafficking of these coagulation factors, it is essential to shed light on the structural basis of the cooperative interplay between ERGIC-53 and MCFD2. The crystallographic data of the CRD of rat ERGIC-53 have revealed that it com...

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Section: Resultsmentioning

confidence: 82%

Section: Methodsmentioning

confidence: 99%

Structural basis for the cooperative interplay between the two causative gene products of combined factor V and factor VIII deficiency

Nishio

Kamiya

Mizushima

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

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“…Crystal structures have been reported for extracellular portions of Fc␥RIIa (18) and Fc␥RIIb (19), suggesting conflicting models for the formation of IgG-Fc⅐Fc␥R complexes. Direct evidence has now been provided from the crystal complex of human IgG1-Fc with recombinant human Fc␥RIII (20), and NMR studies of the interaction of mouse IgG2b-Fc with mouse Fc␥RII (21), demonstrating a 1:1 stoichiometry as the consistent requirement for the expression of Fc effector functions without triggering permanent activation through a single IgG molecule.…”

mentioning

confidence: 99%

Role of Oligosaccharide Residues of IgG1-Fc in FcγRIIb Binding

Mimura¹,

Sondermann²,

Ghirlando³

et al. 2001

Journal of Biological Chemistry

227

159

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Engagement of Fc␥ receptors (Fc␥Rs; ⌬H, ؊6.5 kcal mol ؊1 ; T⌬S, 1.9 kcal mol ؊1 ; ⌬C p , ؊160 cal mol ؊1 K ؊1 ). Removal of terminal galactose residues did not alter the thermodynamic parameters significantly. Outer-arm GlcNAc residues contributed significantly to thermal stability of the C H 2 domains but only slightly to sFc␥RIIb binding. Truncation of 1,3-and 1,6-arm mannose residues generates a linear trisaccharide core structure and resulted in a significantly decreased affinity, a less exothermic ⌬H, and a more negative ⌬C p for sFc␥RIIb binding, which may result from a conformational change coupled to complex formation. Deglycosylation of the C H 2 domains abrogated sFc␥RIIb binding and resulted in the lowest thermal stability accompanied with noncooperative unfolding. These results suggest that truncation of the oligosaccharides of IgG-Fc causes disorder and a closed disposition of the two C H 2 domains, impairing sFc␥RIIb binding.

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“…and therefore bind the ligand only in an aggregated, complexed form [2,3]. Recent reports revealed that the human Fc + R-IgG interaction occurs at a stoichiometry of 1:1, and that the membrane proximal domains of Fc + RII and Fc + RIII participate in binding, while the first domain points away from the cell surface [4,5]. Furthermore, binding of IgG to Fc + R is asymmetric, i.e.…”

Section: Introductionmentioning

confidence: 99%

“…only one of the heavy chains binds, and this explains why IgG can induce receptor aggregation and thus trigger cellular responses only upon being aggregated by antigen. Hence, monomeric IgG present in the circulation does not trigger responses mediated by Fc + RI, Fc + RII or Fc + RIII [4]. Tryptophan residues in the first domain of all Fc + R play an important role in forming a hydrogen bridge with the ligand [6], and both the lower hinge and several residues in the CH2 domain of IgG were shown to participate in the interaction [6][7][8][9][10][11][12][13][14].…”

Section: Introductionmentioning

confidence: 99%

Functional mapping of the FcγRII binding site on human IgG1 by synthetic peptides

et al. 2004

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Receptors specific for the Fc part of IgG (Fc + R) are expressed by several cell types and play diverse roles in immune responses. Impaired function of the activating and inhibitory Fc + R may result in autoimmunity. Thus, the modulation of IgG-Fc + R interaction can be a target for the development of treatments for some autoimmune and inflammatory diseases. This study addresses the localization and functional characterization of linear sequences in human IgG1 which bind to Fc + RII. Peptides with overlapping sequences derived from the CH2 domain of human IgG1 between P 234 and S 298 were synthesized and used in binding and functional experiments. Binding of the peptides to Fc + R was assayed in vitro and ex vivo, and peptides found to interact were functionally tested. The shortest effective peptide was T 256-P 271 complexed by avidin exhibited functional activity; they induced Fc + RIIb-mediated inhibition of the BCR-triggered Ca 2+ response of human Burkitt lymphoma cells, and inflammatory cytokine production (TNF- § and IL-6) by the human monocyte cell line MonoMac. In conclusion, our results suggest that the selected peptides functionally represent the Fc + RII-binding part of IgG1.

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Structural basis of the interaction between IgG and fcγ receptors

Cited by 74 publications

References 48 publications

Structural basis for the cooperative interplay between the two causative gene products of combined factor V and factor VIII deficiency

Structural basis for the cooperative interplay between the two causative gene products of combined factor V and factor VIII deficiency

Role of Oligosaccharide Residues of IgG1-Fc in FcγRIIb Binding

Functional mapping of the FcγRII binding site on human IgG1 by synthetic peptides

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