title: Effect of zinc on human IgG1 and its FcγR interactions.
abstract: In the present study, we show that histidines 310 and 435 at the CH2-CH3 interface of the Fc portion of human IgG1 can coordinate a Zn2+ and participate in the control of the CH2-CH2 interdomain opening. Structures obtained in the absence of Zn2+ have a reduced interdomain gap that likely hamper FcγR binding. This closed conformation of the Fc is stabilized by inter-CH2 domain sugar contacts. Zinc appears to counteract the sugar mediated constriction, suggesting that zinc could be an important control factor in IgG1/FcγR interactions. The results of binding studies performed in the presence of EDTA on FcγR expressing cells supports this hypothesis. When a mutated Fc fragment, in which histidines 310 and 435 have been substituted by lysines (Fc H/K), was compared with the wild-type Fc in crystallographic studies, we found that the mutations leave the interface unaltered but have a long-range effect on the CH2 interdomain separation. Moreover, these substitutions have a differential effect on the binding of IgG1 to Fcγ receptors and their functions. Interaction with the inhibitory FcγRIIB is strongly perturbed by the mutations and mutant IgG1 H/K only weakly engages this receptor. By contrast, higher affinity FcγR are mostly unaffected.
authors.affiliation: INSERM UMR S 872, Centre de Recherche des Cordeliers, Paris, France.
authors.forename: Sophie
authors.initials: S
authors.lastname: Sibéril
authors.forename: Renée
authors.initials: R
authors.lastname: Ménez
authors.forename: Sylvie
authors.initials: S
authors.lastname: Jorieux
authors.forename: Christophe
authors.initials: C
authors.lastname: de Romeuf
authors.forename: Dominique
authors.initials: D
authors.lastname: Bourel
authors.forename: Wolf-Herman
authors.initials: WH
authors.lastname: Fridman
authors.forename: Frédéric
authors.initials: F
authors.lastname: Ducancel
authors.forename: Enrico A
authors.initials: EA
authors.lastname: Stura
authors.forename: Jean-Luc
authors.initials: JL
authors.lastname: Teillaud
mesh_terms: D006801:Humans; D007074:Immunoglobulin G / Q000737:chemistry / Q000276:immunology* / Q000378:metabolism; D019169:Jurkat Cells; D008958:Models, Molecular; D009154:Mutation; D054730:Protein Interaction Domains and Motifs; D017452:Receptors, IgG / Q000737:chemistry / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D015032:Zinc / Q000737:chemistry / Q000378:metabolism*
chemical_list: D007074:Immunoglobulin G; D017452:Receptors, IgG; D015032:Zinc