MHC II-peptide complex conformation constrained by interactions throughout the peptide binding groove determines HLA-DM susceptibility (P5014)
| Autor: | Liusong Yin, Peter Trenh, Lawrence Stern |
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| Rok vydání: | 2013 |
| Předmět: | |
| Zdroj: | The Journal of Immunology. 190:41.8-41.8 |
| ISSN: | 1550-6606 0022-1767 |
| DOI: | 10.4049/jimmunol.190.supp.41.8 |
| Popis: | HLA-DM (DM) mediates the exchange of peptides loaded onto MHC II. However, the determinants of DM-mediated peptide release remain unclear and controversial. In this study, we synthesized a series of peptides derived from HLA-A2104-117 and measured their kinetic stabilities when bound to HLA-DR1 (DR1) in the absence or presence of DM. As expected from previous work, we found that peptides with non-optimal pocket 1 residues were highly DM susceptible. Surprisingly we found that substitution of the pocket 9 residue can counteract the low binding affinity, low kinetic stability and high DM-susceptibility of peptides containing non-optimal pocket 1 residues. Surface Plasmon Resonance demonstrated that DM bound well to DR1 loaded with a peptide variant with pocket 1 alanine (A1), while no binding was observed for a rescue variant with leucine at pocket 9 (A1L9) or for the wild-type peptide (W1Q9). We determined the crystal structure of DR1-A1L9 to 2.3Å resolution, confirming the expected binding frame with alanine at pocket 1. DR1-A1 appeared to adopt a different conformation which can be better detected and edited by DM, as evidenced by the sodium dodecyl sulfate-resistance and recognition by a conformation-specific monoclonal antibody UL-5A1. Together with the results that multiple substitutions influence DM-susceptibility, our data suggest that conformation of MHC II-peptide complex constrained by interactions throughout the peptide binding site determines DM-susceptibility. |
| Databáze: | OpenAIRE |
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