Mechanistic Basis for Epitope Proofreading in the Peptide-Loading Complex

J Immunol. 2015 Nov 1;195(9):4503-13. doi: 10.4049/jimmunol.1501515. Epub 2015 Sep 28.


The peptide-loading complex plays a pivotal role in Ag processing and is thus central to the efficient immune recognition of virally and malignantly transformed cells. The underlying mechanism by which MHC class I (MHC I) molecules sample immunodominant peptide epitopes, however, remains poorly understood. In this article, we delineate the interaction between tapasin (Tsn) and MHC I molecules. We followed the process of peptide editing in real time after ultra-fast photoconversion to pseudoempty MHC I molecules. Tsn discriminates between MHC I loaded with optimal and MHC I bound to suboptimal cargo. This differential interaction is key to understanding the kinetics of epitope proofreading. To elucidate the underlying mechanism at the atomic level, we modeled the Tsn/MHC I complex using all-atom molecular dynamics simulations. We present a catalytic working cycle, in which Tsn binds to MHC I with suboptimal cargo and thereby adjusts the energy landscape in favor of MHC I complexes with immunodominant epitopes.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Sequence
  • Epitopes / chemistry
  • Epitopes / genetics
  • Epitopes / metabolism*
  • Fluorescence Polarization
  • HLA-B44 Antigen / chemistry
  • HLA-B44 Antigen / genetics
  • HLA-B44 Antigen / metabolism
  • Histocompatibility Antigens Class I / chemistry
  • Histocompatibility Antigens Class I / genetics
  • Histocompatibility Antigens Class I / metabolism*
  • Humans
  • Immunodominant Epitopes / chemistry
  • Immunodominant Epitopes / genetics
  • Immunodominant Epitopes / metabolism
  • Kinetics
  • Membrane Transport Proteins / chemistry
  • Membrane Transport Proteins / genetics
  • Membrane Transport Proteins / metabolism*
  • Molecular Dynamics Simulation
  • Mutation
  • Peptides / chemistry
  • Peptides / genetics
  • Peptides / metabolism*
  • Protein Binding
  • Protein Disulfide-Isomerases / chemistry
  • Protein Disulfide-Isomerases / genetics
  • Protein Disulfide-Isomerases / metabolism
  • Protein Structure, Tertiary
  • Thermodynamics


  • Epitopes
  • HLA-B44 Antigen
  • Histocompatibility Antigens Class I
  • Immunodominant Epitopes
  • Membrane Transport Proteins
  • Peptides
  • tapasin
  • Protein Disulfide-Isomerases
  • PDIA3 protein, human