Prediction of immunoglobulin-protein interactions involved in immune response evasion by microorganisms — ASN Events
  1. Schedule
  2. Session 12: Poster Session D - Including Happy Hour & Trade Display
  3. Prediction of immunoglobulin-protein interactions involved in immune response evasion by microorganisms

Prediction of immunoglobulin-protein interactions involved in immune response evasion by microorganisms (#409)

Mark Agostino 1 2 3 , Juan Fernández-Recio 2 , Ricardo L Mancera 1 , Paul A Ramsland 1 3
  1. School of Biomedical Sciences, CHIRI Biosciences, Curtin University, Perth, WA, Australia
  2. Joint BSC-IRB Research Program in Computational Biology, Life Science Department, Barcelona Supercomputing Center, Barcelona, Spain
  3. Centre for Biomedical Research, Burnet Institute, Melbourne, VIC, Australia

Antibodies are key messengers of the immune system. While the antibody variable domains identify antigens, the constant domains of the Fc region (fragment, crystallizable) are often crucial in initiating effector functions. Fc receptors are known against the range of immunoglobulin subtypes and several of these bind to a common region of the Fc: a junction between the two final domains of the heavy chain. Several streptococcal, staphylococcal and malarial proteins also bind to this junction, highlighting a potential mechanism whereby these pathogens may evade the immune response. Structural knowledge is available for some Fc:protein interactions, but not for all systems of interest.1 

In this study, a predictive protein-protein docking simulation protocol is derived, incorporating structural knowledge of Fc:protein interactions, optimized using docking of homology models to reproduce selected known complexes, and then applied to determine models of IgA and IgM with a variety of Fc receptors and pathogenic proteins, including Fcα/μR, PfEMP1 and streptococcal β protein. A consensus model describing the Fc regions involved in protein recognition was derived using the known complexes. The residues of the identified regions are used as restraints following a global docking simulation, with poses satisfying at least a certain number of these retained for rescoring with an optimal scoring potential. The optimized protocol identifies a suitable pose within the top 20 poses in approximately 80% of the test cases.

The determined structures of IgA and IgM with Fcα/μR and the pathogenic proteins provide valuable structural insight into immune modulation by these proteins, as well as suggesting potential strategies for the design of peptides for both therapeutic and antibody purification purposes. Beyond Fc:protein interactions, this study highlights a potentially generally applicable strategy whereby relatively loose restraints for a given class of protein-protein complexes may be derived and applied to significantly improve outcomes in protein-protein docking.

  1. Wines BD, Trist HM, Farrugia W, Ngo C, Trowsdale J, Areschoug T, Lindahl G, Fraser JD, Ramsland PA. (2012) A conserved host and pathogen recognition site on immunoglobulins: structural and functional aspects. Adv Exp Med Biol, 946, p87-112.