Comparative studies of rat IgG to further delineate the Fc: FcRn interaction site

Medesan, Corneliu, Cianga, Petru, Mummert, Mark, Stanescu, Diana, Ghetie, Victor and Ward, E. Sally (1998) Comparative studies of rat IgG to further delineate the Fc: FcRn interaction site. European Journal of Immunology, 28 (7), 2092-2100. (doi:10.1002/(SICI)1521-4141(199807)28:07<2092::AID-IMMU2092>3.0.CO;2-E).

Abstract

Recent data have indicated that the MHC class I-related receptor, FcRn, regulates the half-lives of serum IgG in addition to its known role in transferring IgG from mother to young. In the current study, the activity of rat IgG (rlgG) isotypes in FcRn-mediated functions has been analyzed. The serum half-life and maternofetal transfer in mice decreased in the order rlgG2a > rlgG1 > rlgG2c > rlgG2b. This decrease in activity correlates well with reduced binding affinity for soluble mouse FcRn, and site-directed mutagenesis of a recombinant Fc-hinge fragment has been used to investigate the molecular basis for the differences in activities of the rlgG. Analysis of the serum half-lives of the mutated Fc-hinge fragments demonstrated that, in addition to Ile253, His310, His435 and His436 that were identified in earlier studies, amino acids at positions 257, 307 acid 309 play a role in building the FcRn interaction site of IgG. The study also excludes the involvement of amino acids in a fourth loop located at the CH2-CH3 domain interface that encompasses residues 386-387 in FcRn binding. Sequence differences at positions 257, 307 and 309 between rlgG most likely account for the reduced affinity of rlgG2b and IgG2c relative to rlgG1 and rlgG2a for binding to FcRn.

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Contributors

Author: E. Sally Ward

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