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

Malgorzata Anna Garstka, Susanne Fritzsche, Izabela Lenart, Zeynep Hein, Gytis Jankevicius, Louise H Boyle, Tim Elliott, John Trowsdale, Antony N Antoniou, Martin Zacharias, Sebastian Springer

Research output: Contribution to journalArticlepeer-review

55 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)3989-98
Number of pages10
JournalFASEB Journal
Volume25
Issue number11
DOIs
Publication statusPublished - Nov 2011

Fingerprint

Dive into the research topics of 'Tapasin dependence of major histocompatibility complex class I molecules correlates with their conformational flexibility'. Together they form a unique fingerprint.

Cite this