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Crystal structure of Fc? receptor I and its implication in high affinity ?-immunoglobulin binding.

ABSTRACT: Fc? receptors (Fc?Rs) play critical roles in humoral and cellular immune responses through interactions with the Fc region of immunoglobulin G (IgG). Among them, Fc?RI is the only high affinity receptor for IgG and thus is a potential target for immunotherapy. Here we report the first crystal structure of an Fc?RI with all three extracellular Ig-like domains (designated as D1, D2, and D3). The structure shows that, first, Fc?RI has an acute D1-D2 hinge angle similar to that of Fc?RI but much smaller than those observed in the low affinity Fc? receptors. Second, the D3 domain of Fc?RI is positioned away from the putative IgG binding site on the receptor and is thus unlikely to make direct contacts with Fc. Third, the replacement of Fc?RIII FG-loop ((171)LVGSKNV(177)) with that of Fc?RI ((171)MGKHRY(176)) resulted in a 15-fold increase in IgG(1) binding affinity, whereas a valine insertion in the Fc?RI FG-loop ((171)MVGKHRY(177)) abolished the affinity enhancement. Thus, the Fc?RI FG-loop with its conserved one-residue deletion is critical to the high affinity IgG binding. The structural results support Fc?RI binding to IgG in a similar mode as its low affinity counterparts. Taken together, our study suggests a molecular mechanism for the high affinity IgG recognition by Fc?RI and provides a structural basis for understanding its physiological function and its therapeutic implication in treating autoimmune diseases.

SUBMITTER: Lu J

PROVIDER: S-EPMC3220521 | biostudies-literature | 2011 Nov

REPOSITORIES: biostudies-literature

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Crystal structure of Fcγ receptor I and its implication in high affinity γ-immunoglobulin binding.

Lu Jinghua J Ellsworth Jeff L JL Hamacher Nels N Oak Si Won SW Sun Peter D PD

The Journal of biological chemistry 20110929 47

Fcγ receptors (FcγRs) play critical roles in humoral and cellular immune responses through interactions with the Fc region of immunoglobulin G (IgG). Among them, FcγRI is the only high affinity receptor for IgG and thus is a potential target for immunotherapy. Here we report the first crystal structure of an FcγRI with all three extracellular Ig-like domains (designated as D1, D2, and D3). The structure shows that, first, FcγRI has an acute D1-D2 hinge angle similar to that of FcεRI but much sma ...[more]

PMID: 21965667

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Project description:The Eph receptor tyrosine kinases regulate a variety of physiological and pathological processes not only during development but also in adult organs, and therefore they represent a promising class of drug targets. The EphA4 receptor plays important roles in the inhibition of the regeneration of injured axons, synaptic plasticity, platelet aggregation, and likely in certain types of cancer. Here we report the first crystal structure of the EphA4 ligand-binding domain, which adopts the same jellyroll beta-sandwich architecture as shown previously for EphB2 and EphB4. The similarity with EphB receptors is high in the core beta-stranded regions, whereas large variations exist in the loops, particularly the D-E and J-K loops, which form the high affinity ephrin binding channel. We also used isothermal titration calorimetry, NMR spectroscopy, and computational docking to characterize the binding to EphA4 of two small molecules, 4- and 5-(2,5 dimethyl-pyrrol-1-yl)-2-hydroxybenzoic acid which antagonize ephrin-induced effects in EphA4-expressing cells. We show that the two molecules bind to the EphA4 ligand-binding domain with K(d) values of 20.4 and 26.4 microm, respectively. NMR heteronuclear single quantum coherence titrations revealed that upon binding, both molecules significantly perturb EphA4 residues Ile(31)-Met(32) in the D-E loop, Gln(43) in the E beta-strand, and Ile(131)-Gly(132) in the J-K loop. Molecular docking shows that they can occupy a cavity in the high affinity ephrin binding channel of EphA4 in a similar manner, by interacting mainly with the EphA4 residues in the E strand and D-E and J-K loops. However, many of the interactions observed in Eph receptor-ephrin complexes are absent, which is consistent with the small size of the two molecules and may account for their relatively weak binding affinity. Thus, our studies provide the first published structure of the ligand-binding domain of an EphA receptor of the A subclass. Furthermore, the results demonstrate that the high affinity ephrin binding channel of the Eph receptors is amenable to targeting with small molecule antagonists and suggest avenues for further optimization.

Dataset Information

Crystal structure of Fc? receptor I and its implication in high affinity ?-immunoglobulin binding.

Publications

Crystal structure of Fcγ receptor I and its implication in high affinity γ-immunoglobulin binding.

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