Basis of the Intrinsic Flexibility of the Cε3 Domain of IgE

Allergic reactions are triggered by the interaction between IgE and its high-affinity receptor, Fc epsilon RI. Various studies have mapped the interaction surface between IgE and its cellular receptors to the third constant domain of IgE (C epsilon 3). The isolated C epsilon 3 domain has been shown to exist as a molten globule, and the domain retains significant flexibility within the context of the IgE protein. Here we have analyzed the structural basis of the intrinsic flexibility of this domain. We have compared the sequence of the C epsilon 3 domain to the sequences of other members of the Cl subset of the immunoglobulin superfamily and observed that C epsilon 3 has an unusually high electrostatic charge and an unusually low content of hydrophobic residues. Mutations restoring C epsilon 3 to a more canonical sequence were introduced in an attempt to derive a more structured domain, and several mutants display decreased levels of disorder. Engineered domains of C epsilon 3 with a range of structural rigidities could serve as important tools for the elucidation of the role of flexibility of the C epsilon 3 domain in IgE's biological functions.