Susceptibility to HLA-DM protein is determined by a dynamic conformation of major histocompatibility complex class II molecule bound with peptide
Immunology & Microbiology
Program in Immunology and Microbiology; Department of Pathology
Medical Subject Headings
Amino Acid Sequence; Binding Sites; Crystallography, X-Ray; Enzyme-Linked Immunosorbent Assay; Epitopes; HLA-D Antigens; Humans; Hydrogen Bonding; Kinetics; Models, Molecular; Molecular Sequence Data; Nuclear Magnetic Resonance, Biomolecular; Peptides
Biochemistry | Biochemistry, Biophysics, and Structural Biology | Immunopathology | Structural Biology
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.
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Citation: J Biol Chem. 2014 Aug 22;289(34):23449-64. doi: 10.1074/jbc.M114.585539. Epub 2014 Jul 7. Link to article on publisher's site
The Journal of biological chemistry
Yin, Liusong; Trenh, Peter; Guce, Abigail I.; Wieczorek, Marek; Lange, Sascha; Sticht, Jana; Jiang, Wei; Bylsma, Marissa; Mellins, Elizabeth D.; Freund, Christian; and Stern, Lawrence J., "Susceptibility to HLA-DM protein is determined by a dynamic conformation of major histocompatibility complex class II molecule bound with peptide" (2014). GSBS Student Publications. 1941.