Tapasin dependence of major histocompatibility complex class I molecules correlates with their conformational flexibility
Garstka, Malgorzata Anna, Fritzsche, Susanne, Lenart, Izabela, Hein, Zeynep, Jankevicius, Gytis, Boyle, Louise H., Elliott, Tim, Trowsdale, John, Antoniou, Antony N., Zacharias, Martin and Springer, Sebastian (2011) Tapasin dependence of major histocompatibility complex class I molecules correlates with their conformational flexibility. The FASEB Journal, 25, (11), 3989-3998. (doi:10.1096/fj.11-190249). (PMID:21836024).
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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.
|Keywords:||peptide binding, quality control, ligand binding, natively unstructured proteins|
|Subjects:||Q Science > QH Natural history > QH301 Biology
Q Science > QR Microbiology > QR180 Immunology
|Divisions:||Faculty of Medicine > Cancer Sciences
|Date Deposited:||24 Apr 2012 12:53|
|Last Modified:||26 Apr 2013 05:44|
|Contributors:||Garstka, Malgorzata Anna (Author)
Fritzsche, Susanne (Author)
Lenart, Izabela (Author)
Hein, Zeynep (Author)
Jankevicius, Gytis (Author)
Boyle, Louise H. (Author)
Elliott, Tim (Author)
Trowsdale, John (Author)
Antoniou, Antony N. (Author)
Zacharias, Martin (Author)
Springer, Sebastian (Author)
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