Crystal structure at 2.8 A of an FcRn/heterodimeric Fc complex: mechanism of pH-dependent binding

Mol Cell. 2001 Apr;7(4):867-77. doi: 10.1016/s1097-2765(01)00230-1.

Abstract

The neonatal Fc receptor (FcRn) transports immunoglobulin G (IgG) across epithelia, binding IgG in acidic vesicles (pH < or = 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 A complex structure demonstrates that FcRn uses its alpha2 and beta2-microglobulin domains and carbohydrate to interact with the Fc C(gamma)2-C(gamma)3 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.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Binding Sites / immunology
  • CHO Cells
  • Carbohydrate Metabolism
  • Cricetinae
  • Crystallography
  • Histocompatibility Antigens Class I
  • Humans
  • Hydrogen-Ion Concentration*
  • Immunoglobulin Fc Fragments / metabolism*
  • Immunoglobulin G / metabolism
  • Mutagenesis
  • Protein Structure, Tertiary
  • Rats
  • Receptors, Fc / chemistry*
  • Receptors, Fc / genetics
  • Receptors, Fc / metabolism*

Substances

  • Histocompatibility Antigens Class I
  • Immunoglobulin Fc Fragments
  • Immunoglobulin G
  • Receptors, Fc
  • Fc receptor, neonatal

Associated data

  • PDB/1I1A
  • PDB/1I1C