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J. Biol. Chem., Vol. 281, Issue 41, 30755-30767, October 13, 2006

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An Intermediate pH Unfolding Transition Abrogates the Ability of IgE to Interact with Its High Affinity Receptor FcRI^*

From the Biogen Idec, San Diego, California 92122

The interaction between IgE-Fc (Fc) and its high affinity receptor FcRI on the surface of mast cells and basophils is a key event in allergen-induced allergic inflammation. Recently, several therapeutic strategies have been developed based on this interaction, and some include Fc-containing moieties. Unlike well characterized IgG therapeutics, the stability and folding properties of IgE are not well understood. Here, we present comparative biophysical analyses of the pH stability and thermostability of Fc and IgG1-Fc (Fc). Fc was found to be significantly less stable than Fc under all pH and NaCl conditions tested. Additionally, the C3C4 domains of Fc were shown to become intrinsically unfolded at pH values below 5.0. The interaction between Fc and an Fc-FcRI fusion protein was studied between pH 4.5 and 7.4 using circular dichroism and a combination of differential scanning calorimetry and isothermal titration calorimetry. Under neutral pH conditions, the apparent affinity of Fc for the dimeric fusion protein was extremely high compared with published values for the monomeric receptor (K_D < 10^-12 M). Titration to pH 6.0 did not significantly change the binding affinity, and titration to pH 5.5 only modestly attenuated affinity. At pH values below 5.0, the receptor binding domains of Fc unfolded, and interaction of Fc with the Fc-FcRI fusion protein was abrogated. The unusual pH sensitivity of Fc may play a role in antigen-dependent regulation of receptor-bound, non-circulating IgE.

Received for publication, May 31, 2006 , and in revised form, July 25, 2006.

^* The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ To whom correspondence should be addressed. Dept. of Protein Chemistry, Biogen Idec, 5200 Research Place, San Diego, CA 92122. Tel.: 858-401-5261; Fax: 858-401-5031; E-mail: stephen.demarest{at}biogenidec.com.

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