Abstract
The neonatal Fc receptor (FcRn) transports immunoglobulin G (IgG) across epithelia, binding IgG in acidic vesicles (pH ≤ 6.5) and releasing IgG in the blood at pH 7.4. Well-ordered FcRn/Fc crystals are prevented by the formation of “oligomeric ribbons” of FcRn dimers bridged by Fc homodimers, thus we crystallized a 1:1 complex between rat FcRn and a heterodimeric Fc containing only one FcRn binding site. The 2.8 Å complex structure demonstrates that FcRn uses its α2 and β2-microglobulin domains and carbohydrate to interact with the Fc C γ2–C γ3 interface. The structure reveals conformational changes in Fc and three titratable salt bridges that confer pH-dependent binding, and can be used to guide rational design of therapeutic IgGs with longer serum half-lives.
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