| Content Provider |
World Health Organization (WHO)-Global Index Medicus |
| Author |
Lange, Sascha Stern, Lawrence J. Guce, Abigail Wieczorek, Marek Bylsma, Marissa Trenh, Peter Jiang, Wei Freund, Christian Sticht, Jana Yin, Liusong Mellins, Elizabeth D. |
| Description |
Author Affiliation: Yin L ( From the Program in Immunology and Microbiology and.); Trenh P ( From the Program in Immunology and Microbiology and.); Guce A ( Department of Pathology, University of Massachusetts Medical School, Worcester, Massachusetts 01605.); Wieczorek M ( the Institute of Chemistry and Biochemistry, Freie Universität Berlin, Thielallee 63, 14195 Berlin, Germany, and.); Lange S ( the Institute of Chemistry and Biochemistry, Freie Universität Berlin, Thielallee 63, 14195 Berlin, Germany, and.); Sticht J ( the Institute of Chemistry and Biochemistry, Freie Universität Berlin, Thielallee 63, 14195 Berlin, Germany, and.); Jiang W ( the Department of Pediatrics, Program in Immunology, Stanford University Medical Center, Stanford, California 94305.); Bylsma M ( Department of Pathology, University of Massachusetts Medical School, Worcester, Massachusetts 01605.); Mellins ED ( the Department of Pediatrics, Program in Immunology, Stanford University Medical Center, Stanford, California 94305.); Freund C ( the Institute of Chemistry and Biochemistry, Freie Universität Berlin, Thielallee 63, 14195 Berlin, Germany, and.); Stern LJ ( From the Program in Immunology and Microbiology and Department of Pathology, University of Massachusetts Medical School, Worcester, Massachusetts 01605, lawrence.stern@umassmed.edu.) |
| Abstract |
HLA-DM mediates the exchange of peptides loaded onto MHCII molecules during antigen presentation by a mechanism that remains unclear and controversial. Here, we investigated the sequence and structural determinants of HLA-DM interaction. Peptides interacting nonoptimally in the P1 pocket exhibited low MHCII binding affinity and kinetic instability and were highly susceptible to HLA-DM-mediated peptide exchange. These changes were accompanied by conformational alterations detected by surface plasmon resonance, SDS resistance assay, antibody binding assay, gel filtration, dynamic light scattering, small angle x-ray scattering, and NMR spectroscopy. Surprisingly, all of those changes could be reversed by substitution of the P9 pocket anchor residue. Moreover, MHCII mutations outside the P1 pocket and the HLA-DM interaction site increased HLA-DM susceptibility. These results indicate that a dynamic MHCII conformational determinant rather than P1 pocket occupancy is the key factor determining susceptibility to HLA-DM-mediated peptide exchange and provide a molecular mechanism for HLA-DM to efficiently target unstable MHCII-peptide complexes for editing and exchange those for more stable ones. |
| ISSN |
00219258 |
| e-ISSN |
1083351X |
| Journal |
Journal of Biological Chemistry |
| Issue Number |
34 |
| Volume Number |
289 |
| Language |
English |
| Publisher |
American Society for Biochemistry and Molecular Biology (United States) |
| Publisher Date |
2014-08-22 |
| Publisher Place |
United States |
| Access Restriction |
Open |
| Subject Keyword |
Epitopes Immunology HLA-D Antigens Peptides Amino Acid Sequence Binding Sites Crystallography, X-Ray Enzyme-Linked Immunosorbent Assay Chemistry Hydrogen Bonding Kinetics Models, Molecular Molecular Sequence Data Nuclear Magnetic Resonance, Biomolecular Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't Research Support, U.S. Gov't, Non-P.H.S. Biochemistry Molecular Biology |
| Content Type |
Text |
| Resource Type |
Article |
| Subject |
Cell Biology Biochemistry Molecular Biology |
