Selector function of MHC I molecules is determined by protein plasticity

Sci Rep. 2015 Oct 20;5:14928. doi: 10.1038/srep14928.

Abstract

The selection of peptides for presentation at the surface of most nucleated cells by major histocompatibility complex class I molecules (MHC I) is crucial to the immune response in vertebrates. However, the mechanisms of the rapid selection of high affinity peptides by MHC I from amongst thousands of mostly low affinity peptides are not well understood. We developed computational systems models encoding distinct mechanistic hypotheses for two molecules, HLA-B*44:02 (B*4402) and HLA-B*44:05 (B*4405), which differ by a single residue yet lie at opposite ends of the spectrum in their intrinsic ability to select high affinity peptides. We used in vivo biochemical data to infer that a conformational intermediate of MHC I is significant for peptide selection. We used molecular dynamics simulations to show that peptide selector function correlates with protein plasticity, and confirmed this experimentally by altering the plasticity of MHC I with a single point mutation, which altered in vivo selector function in a predictable way. Finally, we investigated the mechanisms by which the co-factor tapasin influences MHC I plasticity. We propose that tapasin modulates MHC I plasticity by dynamically coupling the peptide binding region and α3 domain of MHC I allosterically, resulting in enhanced peptide selector function.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alleles
  • Antigen Presentation*
  • Binding Sites
  • HLA-B44 Antigen / chemistry
  • HLA-B44 Antigen / genetics
  • HLA-B44 Antigen / immunology
  • HLA-B44 Antigen / metabolism
  • Histocompatibility Antigens Class I / chemistry
  • Histocompatibility Antigens Class I / genetics
  • Histocompatibility Antigens Class I / immunology*
  • Histocompatibility Antigens Class I / metabolism*
  • Humans
  • Membrane Transport Proteins / chemistry
  • Membrane Transport Proteins / metabolism
  • Models, Molecular
  • Peptides / chemistry
  • Peptides / immunology*
  • Peptides / metabolism*
  • Protein Binding
  • Protein Conformation

Substances

  • HLA-B44 Antigen
  • Histocompatibility Antigens Class I
  • Membrane Transport Proteins
  • Peptides
  • tapasin