Tapasin dependence of major histocompatibility complex class I molecules correlates with their conformational flexibility
| Autor: | Antony N. Antoniou, Gytis Jankevicius, Malgorzata A. Garstka, Susanne Fritzsche, Louise H. Boyle, John Trowsdale, Tim Elliott, Izabela Lenart, Zeynep Hein, Martin Zacharias, Sebastian Springer |
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| Rok vydání: | 2011 |
| Předmět: |
Protein Conformation
Peptide Peptide binding Plasma protein binding Immunodominance Molecular Dynamics Simulation Major histocompatibility complex Biochemistry Cell Line HLA-B44 Antigen 03 medical and health sciences Molecular dynamics 0302 clinical medicine Tapasin Genetics Humans Molecular Biology 030304 developmental biology chemistry.chemical_classification 0303 health sciences biology Histocompatibility Antigens Class I Membrane Transport Proteins chemistry Chaperone (protein) biology.protein Biophysics Protein Binding 030215 immunology Biotechnology |
| Zdroj: | The FASEB Journal. 25:3989-3998 |
| ISSN: | 1530-6860 0892-6638 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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