Peptide exchange on MHC-I by TAPBPR is driven by a negative allostery release cycle

Nat Chem Biol. 2018 Aug;14(8):811-820. doi: 10.1038/s41589-018-0096-2. Epub 2018 Jul 9.


Chaperones TAPBPR and tapasin associate with class I major histocompatibility complexes (MHC-I) to promote optimization (editing) of peptide cargo. Here, we use solution NMR to investigate the mechanism of peptide exchange. We identify TAPBPR-induced conformational changes on conserved MHC-I molecular surfaces, consistent with our independently determined X-ray structure of the complex. Dynamics present in the empty MHC-I are stabilized by TAPBPR and become progressively dampened with increasing peptide occupancy. Incoming peptides are recognized according to the global stability of the final pMHC-I product and anneal in a native-like conformation to be edited by TAPBPR. Our results demonstrate an inverse relationship between MHC-I peptide occupancy and TAPBPR binding affinity, wherein the lifetime and structural features of transiently bound peptides control the regulation of a conformational switch located near the TAPBPR binding site, which triggers TAPBPR release. These results suggest a similar mechanism for the function of tapasin in the peptide-loading complex.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Allosteric Regulation*
  • Histocompatibility Antigens Class I / chemistry
  • Histocompatibility Antigens Class I / metabolism*
  • Humans
  • Immunoglobulins / chemistry
  • Immunoglobulins / metabolism*
  • Membrane Proteins / chemistry
  • Membrane Proteins / metabolism*
  • Peptides / chemistry
  • Peptides / metabolism*
  • Protein Conformation


  • Histocompatibility Antigens Class I
  • Immunoglobulins
  • Membrane Proteins
  • Peptides
  • TAPBPL protein, human