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

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.—Garstka, M. A., Fritzsche, S., Lenart, I., Hein, Z., Jankevicius, G., Boyle, L. H., Elliott, T., Trowsdale, J., Antoniou, A. N., Zacharias, M., Springer, S. Tapasin dependence of major histocompatibility complex class I molecules correlates with their conformational flexibility. FASEB J. 25, 3989–3998 (2011). www.fasebj.org