Anchor side chains of short peptide fragments trigger ligand-exchange of class II MHC molecules.
Class II MHC molecules display peptides on the cell surface for the surveillance by CD4+ T cells. To ensure that these ligands accurately reflect the content of the intracellular MHC loading compartment, a complex processing pathway has evolved that delivers only stable peptide/MHC complexes to the surface. As additional safeguard, MHC molecules quickly acquire a 'non-receptive' state once they have lost their ligand. Here we show now that amino acid side chains of short peptides can bypass these safety mechanisms by triggering the reversible ligand-exchange. The catalytic activity of dipeptides such as Tyr-Arg was stereo-specific and could be enhanced by modifications addressing the conserved H-bond network near the P1 pocket of the MHC molecule. It affected both antigen-loading and ligand-release and strictly correlated with reported anchor preferences of P1, the specific target site for the catalytic side chain of the dipeptide. The effect was evident also in CD4+ T cell assays, where the allele-selective influence of the dipeptides translated into increased sensitivities of the antigen-specific immune response. Molecular dynamic calculations support the hypothesis that occupation of P1 prevents the 'closure' of the empty peptide binding site into the non-receptive state. During antigen-processing and -presentation P1 may therefore function as important "sensor" for peptide-load. While it regulates maturation and trafficking of the complex, on the cell surface, short protein fragments present in blood or lymph could utilize this mechanism to alter the ligand composition on antigen presenting cells in a catalytic way.
Gupta
Shashank
S
Max-Delbrück-Center for Molecular Medicine, Berlin, Germany.
Höpner
Sabine
S
Rupp
Bernd
B
Günther
Sebastian
S
Dickhaut
Katharina
K
Agarwal
Noopur
N
Cardoso
M Cristina
MC
Kühne
Ronald
R
Wiesmüller
Karl-Heinz
KH
Jung
Günther
G
Falk
Kirsten
K
Rötzschke
Olaf
O
D000949:Histocompatibility Antigens Class II / Q000737:chemistry*; D007700:Kinetics; D008024:Ligands; D010446:Peptide Fragments / Q000737:chemistry*; D013329:Structure-Activity Relationship
D000949:Histocompatibility Antigens Class II; D008024:Ligands; D010446:Peptide Fragments