title: Structural requirements for the interaction of human IgM and IgA with the human Fcalpha/mu receptor.
abstract: Here we unravel the structural features of human IgM and IgA that govern their interaction with the human Fcalpha/mu receptor (hFcalpha/muR). Ligand polymerization status was crucial for the interaction, because hFcalpha/muR binding did not occur with monomeric Ab of either class. hFcalpha/muR bound IgM with an affinity in the nanomolar range, whereas the affinity for dimeric IgA (dIgA) was tenfold lower. Panels of mutant IgM and dIgA were used to identify regions critical for hFcalpha/muR binding. IgM binding required contributions from both Cmu3 and Cmu4 Fc domains, whereas for dIgA, an exposed loop in the Calpha3 domain was crucial. This loop, comprising residues Pro440-Phe443, lies at the Fc domain interface and has been implicated in the binding of host receptors FcalphaRI and polymeric Ig receptor (pIgR), as well as IgA-binding proteins produced by certain pathogenic bacteria. Substitutions within the Pro440-Phe443 loop resulted in loss of hFcalpha/muR binding. Furthermore, secretory component (SC, the extracellular portion of pIgR) and bacterial IgA-binding proteins were shown to inhibit the dIgA-hFcalpha/muR interaction. Therefore, we have identified a motif in the IgA-Fc inter-domain region critical for hFcalpha/muR interaction, and highlighted the multi-functional nature of a key site for protein-protein interaction at the IgA Fc domain interface.
authors.affiliation: Institute of Genetics, Queens Medical Centre, University of Nottingham, Nottingham, UK.
authors.forename: Ashfaq
authors.initials: A
authors.lastname: Ghumra
authors.forename: Jianguo
authors.initials: J
authors.lastname: Shi
authors.forename: Richard S
authors.initials: RS
authors.lastname: Mcintosh
authors.forename: Ingunn B
authors.initials: IB
authors.lastname: Rasmussen
authors.forename: Ranveig
authors.initials: R
authors.lastname: Braathen
authors.forename: Finn-Eirik
authors.initials: FE
authors.lastname: Johansen
authors.forename: Inger
authors.initials: I
authors.lastname: Sandlie
authors.forename: Patricia K
authors.initials: PK
authors.lastname: Mongini
authors.forename: Thomas
authors.initials: T
authors.lastname: Areschoug
authors.forename: Gunnar
authors.initials: G
authors.lastname: Lindahl
authors.forename: Melanie J
authors.initials: MJ
authors.lastname: Lewis
authors.forename: Jenny M
authors.initials: JM
authors.lastname: Woof
authors.forename: Richard J
authors.initials: RJ
authors.lastname: Pleass
mesh_terms: D020816:Amino Acid Motifs; D019943:Amino Acid Substitution; D000818:Animals; D000915:Antibody Affinity / Q000235:genetics / Q000276:immunology; D019556:COS Cells; D002522:Chlorocebus aethiops; D006801:Humans; D007070:Immunoglobulin A / Q000737:chemistry* / Q000235:genetics / Q000276:immunology; D007075:Immunoglobulin M / Q000737:chemistry* / Q000235:genetics / Q000276:immunology; D050505:Mutant Proteins / Q000276:immunology; D009154:Mutation; D054730:Protein Interaction Domains and Motifs / Q000276:immunology; D055503:Protein Multimerization; D017434:Protein Structure, Tertiary; D011961:Receptors, Fc / Q000235:genetics / Q000276:immunology*
chemical_list: C526790:Fcalpha-mu receptor, human; D007070:Immunoglobulin A; D007075:Immunoglobulin M; D050505:Mutant Proteins; D011961:Receptors, Fc