Tapasin dependence of major histocompatibility complex class I molecules correlates with their conformational flexibility

FASEB J. 2011 Nov;25(11):3989-98. doi: 10.1096/fj.11-190249. Epub 2011 Aug 11.


Major histocompatibility complex (MHC) class I molecules present cell internally derived peptides at the plasma membrane for surveillance by cytotoxic T lymphocytes. The surface expression of most class I molecules at least partially depends on the endoplasmic reticulum protein, tapasin, which helps them to bind peptides of the right length and sequence. To determine what makes a class I molecule dependent on support by tapasin, we have conducted in silico molecular dynamics (MD) studies and laboratory experiments to assess the conformational state of tapasin-dependent and -independent class I molecules. We find that in the absence of peptide, the region around the F pocket of the peptide binding groove of the tapasin-dependent molecule HLA-B*44:02 is in a disordered conformational state and that it is converted to a conformationally stable state by tapasin. This novel chaperone function of tapasin has not been described previously. We demonstrate that the disordered state of class I is caused by the presence of two adjacent acidic residues in the bottom of the F pocket of class I, and we suggest that conformational disorder is a common feature of tapasin-dependent class I molecules, making them essentially unable to bind peptides on their own. MD simulations are a useful tool to predict such conformational disorder of class I molecules.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cell Line
  • HLA-B44 Antigen / immunology
  • Histocompatibility Antigens Class I / chemistry*
  • Histocompatibility Antigens Class I / drug effects
  • Humans
  • Membrane Transport Proteins / pharmacology*
  • Molecular Dynamics Simulation
  • Protein Binding
  • Protein Conformation / drug effects*


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