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Molecular mechanism of pH dependent antibody binding: Structure/function studies on the neonatal Fc receptor

Citation

Vaughn, Daniel E. (1998) Molecular mechanism of pH dependent antibody binding: Structure/function studies on the neonatal Fc receptor. Dissertation (Ph.D.), California Institute of Technology. http://resolver.caltech.edu/CaltechTHESIS:08062012-111300229

Abstract

The work described here is an investigation of the molecular mechanism of pH dependent immunoglobulin G (IgG) binding by the neonatal Fc receptor (FcRn). FcRn binds IgG at acidic, but not alkaline pHs, in two important physiological processes. These processes are the acquisition of passive immunity by the fetus or newborn and protecting IgG from a default degradative pathway.

A biosensor assay is used to characterize the interaction of a soluble form of FcRn with IgG. Immobilization of FcRn on the biosensor surface reproduces the high affinity IgG binding observed for membrane bound FcRn, whereas immobilization of IgG results in lower affinity binding similar to that of the FcRn/IgG interaction in solution. The statistical method of cross-validation is used to show that there are two classes of noninteracting binding sites. The IgG binding interaction is characterized for several mutant FcRns with designed amino acid substitutions. These mutations map the functional IgG binding site on FcRn.

The structure of FcRn at an alkaline pH is described. This structure determination reveals an extensive carbohydrate mediated interaction between the dimer related FeRn molecules. The physiological relevance of this interaction is discussed in the context of the FcRn dimerization literature. A further refined structure of FcRn at an acidic pH is described that includes additional carbohydrate structure. These structures are compared with specific attention to the pH dependence of FcRn stability and IgG affinity. Finally, a mechanism for pH dependent antibody binding to FcRn is proposed based on these structures and the body of structure/function literature concerning this interaction.

Item Type:Thesis (Dissertation (Ph.D.))
Subject Keywords:Biology
Degree Grantor:California Institute of Technology
Division:Biology
Major Option:Biology
Thesis Availability:Restricted to Caltech community only
Research Advisor(s):
  • Bjorkman, Pamela J.
Thesis Committee:
  • Unknown, Unknown
Defense Date:7 July 1997
Record Number:CaltechTHESIS:08062012-111300229
Persistent URL:http://resolver.caltech.edu/CaltechTHESIS:08062012-111300229
Default Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:7182
Collection:CaltechTHESIS
Deposited By: Benjamin Perez
Deposited On:06 Aug 2012 21:19
Last Modified:15 Jan 2013 22:24

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