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Structural requirements for the interaction of human IgM and IgA with the human Fc alpha/mu receptor

Ghumra, Ashfaq; Shi, Jianguo; Mcintosh, Richard S.; Rasmussen, Ingunn B.; Braathen, Ranveig; Johansen, Finn-Eirik; Sandlie, Inger; Mongini, Patricia K.; Areschoug, Thomas LU and Lindahl, Gunnar LU , et al. (2009) In European Journal of Immunology 39(4). p.1147-1156
Abstract
Here we unravel the structural features of human IgM and IgA that govern their interaction with the human Fc alpha/mu receptor (hFc alpha/mu R). Ligand polymerization status was crucial for the interaction, because hFc alpha/mu R binding did not occur with monomeric Ab of either class. hFc alpha/mu R 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 hFc alpha/mu R binding. IgM binding required contributions from both C mu 3 and C mu 4 Fc domains, whereas for dIgA, an exposed loop in the C alpha 3 domain was crucial. This loop, comprising residues Pro440-Phe443, lies at the Fc domain interface and has been... (More)
Here we unravel the structural features of human IgM and IgA that govern their interaction with the human Fc alpha/mu receptor (hFc alpha/mu R). Ligand polymerization status was crucial for the interaction, because hFc alpha/mu R binding did not occur with monomeric Ab of either class. hFc alpha/mu R 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 hFc alpha/mu R binding. IgM binding required contributions from both C mu 3 and C mu 4 Fc domains, whereas for dIgA, an exposed loop in the C alpha 3 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 Fc alpha RI 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 hFc alpha/mu R binding. Furthermore, secretory component (SC, the extracellular portion of pIgR) and bacterial IgA-binding proteins were shown to inhibit the dIgA-hFc alpha/mu R interaction. Therefore, we have identified a motif in the IgA-Fc inter-domain region critical for hFc alpha/mu R interaction, and highlighted the multi-functional nature of a key site for protein-protein interaction at the IgA Fc domain interface. (Less)
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Contribution to journal
publication status
published
subject
keywords
Human Fc alpha/mu receptor, IgA, IgM
in
European Journal of Immunology
volume
39
issue
4
pages
1147 - 1156
publisher
John Wiley & Sons
external identifiers
  • wos:000265478700025
  • scopus:65449156532
ISSN
1521-4141
DOI
10.1002/eji.200839184
language
English
LU publication?
yes
id
42ca7f18-68fd-447e-b88d-47ea2325ba1e (old id 1399542)
date added to LUP
2009-06-15 15:19:13
date last changed
2017-11-12 03:18:37
@article{42ca7f18-68fd-447e-b88d-47ea2325ba1e,
  abstract     = {Here we unravel the structural features of human IgM and IgA that govern their interaction with the human Fc alpha/mu receptor (hFc alpha/mu R). Ligand polymerization status was crucial for the interaction, because hFc alpha/mu R binding did not occur with monomeric Ab of either class. hFc alpha/mu R 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 hFc alpha/mu R binding. IgM binding required contributions from both C mu 3 and C mu 4 Fc domains, whereas for dIgA, an exposed loop in the C alpha 3 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 Fc alpha RI 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 hFc alpha/mu R binding. Furthermore, secretory component (SC, the extracellular portion of pIgR) and bacterial IgA-binding proteins were shown to inhibit the dIgA-hFc alpha/mu R interaction. Therefore, we have identified a motif in the IgA-Fc inter-domain region critical for hFc alpha/mu R interaction, and highlighted the multi-functional nature of a key site for protein-protein interaction at the IgA Fc domain interface.},
  author       = {Ghumra, Ashfaq and Shi, Jianguo and Mcintosh, Richard S. and Rasmussen, Ingunn B. and Braathen, Ranveig and Johansen, Finn-Eirik and Sandlie, Inger and Mongini, Patricia K. and Areschoug, Thomas and Lindahl, Gunnar and Lewis, Melanie J. and Woof, Jenny M. and Pleass, Richard J.},
  issn         = {1521-4141},
  keyword      = {Human Fc alpha/mu receptor,IgA,IgM},
  language     = {eng},
  number       = {4},
  pages        = {1147--1156},
  publisher    = {John Wiley & Sons},
  series       = {European Journal of Immunology},
  title        = {Structural requirements for the interaction of human IgM and IgA with the human Fc alpha/mu receptor},
  url          = {http://dx.doi.org/10.1002/eji.200839184},
  volume       = {39},
  year         = {2009},
}