Differential peptide dynamics is linked to major histocompatibility complex polymorphism.
Peptide presentation by major histocompatibility complex (MHC) molecules is of central importance for immune responses, which are triggered through recognition of peptide-loaded MHC molecules (pMHC) by cellular ligands such as T-cell receptors (TCR). However, a unifying link between structural features of pMHC and cellular responses has not been established. Instead, pMHC/TCR binding studies suggest conformational and/or flexibility changes of the binding partners as a possible cause of differential T-cell stimulation, but information on real-time dynamics is lacking. We therefore probed the real-time dynamics of a MHC-bound nonapeptide (m9), by combining time-resolved fluorescence depolarization and molecular dynamics simulations. Here we show that the nanosecond dynamics of this peptide presented by two human MHC class I subtypes (HLA-B*2705 and HLA-B*2709) with differential autoimmune disease association varies dramatically, despite virtually identical crystal structures. The peptide dynamics is linked to the single, buried polymorphic residue 116 in the peptide binding groove. Pronounced peptide flexibility is seen only for the non-disease-associated subtype HLA-B*2709, suggesting an entropic control of peptide recognition. Thermodynamic data obtained for two additional peptides support this hypothesis.
Pöhlmann
Thomas
T
Department of Physics, Freie Universität Berlin, Arnimallee 14, D-14195 Berlin, Germany.
Böckmann
Rainer A
RA
Grubmüller
Helmut
H
Uchanska-Ziegler
Barbara
B
Ziegler
Andreas
A
Alexiev
Ulrike
U
D019277:Entropy; D015235:HLA-B Antigens / Q000737:chemistry / Q000378:metabolism; D015796:HLA-B27 Antigen; D006801:Humans; D007700:Kinetics; D008285:Major Histocompatibility Complex / Q000235:genetics*; D008856:Microscopy, Fluorescence; D008958:Models, Molecular; D015233:Models, Statistical; D010455:Peptides / Q000737:chemistry*; D011110:Polymorphism, Genetic; D011485:Protein Binding; D011487:Protein Conformation; D013050:Spectrometry, Fluorescence; D013601:T-Lymphocytes / Q000378:metabolism; D013696:Temperature; D013816:Thermodynamics; D013997:Time Factors
D015235:HLA-B Antigens; C464937:HLA-B*27:09 antigen; D015796:HLA-B27 Antigen; D010455:Peptides