Title: Phosphorylationdependant interaction between antigenic peptides and MHC class 1: a molecular basis f
1Phosphorylation-dependant interaction between
antigenic peptides and MHC class 1 a molecular
basis for the presentation of transformed
selfFiyaz Mohammed et al. Nature Immunology
Volume 9, No. 11, November 2008
www.pnas.org/content/100/15.cover-expansion
- P. Mistry O. Parsons A. Prashar K. Wright
2 Aim
- Can phosphorylation increase peptide binding
affinity for HLA-A2? - Major histocompatibility complexes (MHC) play an
important role in immunity. - Situated on the cell surface
- Changes in normal cell
- functioning can lead to
- altered self to the
- immune system
Fig3-15 Immunology, 7ed. (Garland Science 2008)
3 Introduction
- MHCs interact with CD8 and T cells, which leads
to cytolytic activity - Evidence peptides containing post-translational
modification (PTM) contribute to the pool of
MHC-bound peptides thus represent potential
targets for T cell recognition. - Phosphopeptide antigens therapeutic interest
deregulation of protein kinase activity is one of
the hallmarks of malignant transformation - MHC class 1 bound phosphopeptides represent a
new set of target antigens for cancer
immunotherapy
4Unusual characteristics of HLA2-A2-bound
phosphopeptides
- 1) 68 of p-Ser/p-Thr at P4 alone
- 2) 62 had Arg/Lys at P1
- 3) In predicted HLA-A2 binding proteins, no bias
for P4 phosphorylation
- Affinities of phosphopeptides greater - Most
notable in peptides phosphorylated at P4 - Arg
(R) at P1 also increased binding affinity -
Presence of PC anchor residues also increased
affinity
5Phosphate-mediated phosphopeptide and HLA-A2
contacts
- Normal MHC-peptide complex structure conserved,
with extended conformation on peptide - Stabilizing interactions conserved
- P4 p-Ser exposed to solvent, available for
contact with TCR - Electrostatic interactions between a1 domain and
Arg65 - p-Ser stabilized by conserved H20 molecule
- H-bonds between p-Ser, P2 carbonyl P1 Arg
residue
6Subdominant anchor interactions are structurally
suboptimal
- Dominant P2 Leu anchor residue fills B pocket
optimally provides H-bond ints.
Compared to
Met Thr
Gln
7Energetic basis of phosphopeptide binding to
HLA-A2
- Phosphopeptide RQApSIELPSM.
- Phosphorylated peptide 150-fold ? affinity for
HLA-A2 than nonphosphorylated. With only slightly
? binding to HLA-A2-R65A. - Substitution of P1 R?A in phosphopeptide caused
only 5-fold ? in affinity for HLA-A2. With much ?
affinity for HLA-A2-R65A. - Reorientation of pS moiety may ? energetic
contribution of interaction, explaining modest
effects of mutations of P1/HLA-A2
8Effect of the phosphate moiety on TCR
recognition
- Phosphate is close to CDR3a loop on TCR, suggests
TCR directly recognises phosphate moiety.
- CDR3ß loop is adjacent to C-terminal central
sections of peptide. - Phosphorylation may affect TCR ints indirectly
as constraint at P4 resulting in differences in
P5-PC region.
9Discussion
- Fiyaz Mohammed et al. demonstrate entirely new
method for MHC binding - No insertion of amino acid into pocket in peptide
binding cleft - Instead, interactions occur between P1 side
chain/P4 phosphate moiety and MHC surface - Phosphate surface anchor
- Only canonical P1 arginine/lysine, P4 phosphate
moiety demonstrates increase in peptide
presentation - Phosphorylation at other amino acids has no
effect on peptide MHC presentation.
10Discussion
- Peptide phosphorylation at P4 increases
presentation by MHCs - Deregulated phosphorylationpresentation of
peptide antigens not presented on normal cells. - P4 phosphate moiety has several functions
- Models indicate that P4 phosphate moiety binds
CDR3a loop of TCR - Constrains structure of peptide from P5-PCleads
to MHC presentation of novel phosphopeptides