Crystal structure at 2.8 A of an FcRn/heterodimeric Fc complex: mechanism of pH-dependent binding.
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.
Martin
W L
WL
Division of Biology, California Institute of Technology, Pasadena, CA 91125, USA.
West
A P
AP
Gan
L
L
Bjorkman
P J
PJ
D000818:Animals; D001665:Binding Sites / Q000276:immunology; D016466:CHO Cells; D050260:Carbohydrate Metabolism; D006224:Cricetinae; D003461:Crystallography; D015395:Histocompatibility Antigens Class I; D006801:Humans; D006863:Hydrogen-Ion Concentration; D007141:Immunoglobulin Fc Fragments / Q000378:metabolism*; D007074:Immunoglobulin G / Q000378:metabolism; D016296:Mutagenesis; D017434:Protein Structure, Tertiary; D051381:Rats; D011961:Receptors, Fc / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*
D015395:Histocompatibility Antigens Class I; D007141:Immunoglobulin Fc Fragments; D007074:Immunoglobulin G; D011961:Receptors, Fc; C100688:Fc receptor, neonatal