title: 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.
authors.affiliation: Molecular Life Science, Jacobs University Bremen, Bremen, Germany.
authors.forename: Malgorzata Anna
authors.initials: MA
authors.lastname: Garstka
authors.forename: Susanne
authors.initials: S
authors.lastname: Fritzsche
authors.forename: Izabela
authors.initials: I
authors.lastname: Lenart
authors.forename: Zeynep
authors.initials: Z
authors.lastname: Hein
authors.forename: Gytis
authors.initials: G
authors.lastname: Jankevicius
authors.forename: Louise H
authors.initials: LH
authors.lastname: Boyle
authors.forename: Tim
authors.initials: T
authors.lastname: Elliott
authors.forename: John
authors.initials: J
authors.lastname: Trowsdale
authors.forename: Antony N
authors.initials: AN
authors.lastname: Antoniou
authors.forename: Martin
authors.initials: M
authors.lastname: Zacharias
authors.forename: Sebastian
authors.initials: S
authors.lastname: Springer
mesh_terms: D002460:Cell Line; D059948:HLA-B44 Antigen / Q000276:immunology; D015395:Histocompatibility Antigens Class I / Q000737:chemistry* / Q000187:drug effects; D006801:Humans; D026901:Membrane Transport Proteins / Q000494:pharmacology*; D056004:Molecular Dynamics Simulation; D011485:Protein Binding; D011487:Protein Conformation / Q000187:drug effects*
chemical_list: D059948:HLA-B44 Antigen; D015395:Histocompatibility Antigens Class I; D026901:Membrane Transport Proteins; C107762:tapasin