PMID- 14617029
OWN - NLM
STAT- MEDLINE
DCOM- 20040722
LR  - 20190827
IS  - 0001-2815 (Print)
IS  - 0001-2815 (Linking)
VI  - 62
IP  - 6
DP  - 2003 Dec
TI  - Detailed analysis of the effects of Glu/Lys beta69 human leukocyte antigen-DP 
      polymorphism on peptide-binding specificity.
PG  - 459-71
AB  - The polymorphism at position beta69 of the human leukocyte antigen (HLA)-DP 
      molecule has been associated with susceptibility to several immune disorders and 
      alloreactivity. Using molecular modeling, we have predicted a detailed structure 
      of the HLA-DP2 molecule (carrying Glubeta69) complexed with class II associated 
      invariant chain derived peptide (CLIP) and compared it with the form carrying Lys 
      at beta69 (HLA-DP2K69). Major changes between the two models were observed in the 
      shape and charge distribution of pocket 4 and of the nearby pocket 6. 
      Consequently, we analyzed in detail the peptide-binding specificities of both 
      HLA-DP molecules expressed as recombinant proteins. We first determined that the 
      minimum peptide-binding core of CLIP for both HLA-DP2 and DP2K69 is represented 
      by nine aminoacids corresponding to the sequence 91-99 of invariant chain (Ii). 
      We then assessed the peptide-binding specificities of the two pockets and 
      determined the role of position beta69, using competition tests with the 
      Ii-derived peptide CLIP and its mutated forms carrying all the aminoacidic 
      substitutions in P4 and P6. Pocket 4 of HLA-DP2 showed high affinity for 
      positively charged, aromatic, and polar residues, whereas aliphatic residues were 
      disfavored. Pocket 4 of the DP2K69 variant showed a reduced aminoacid selectivity 
      with aromatic residues most preferred. Pocket 6 of HLA-DP2 showed high affinity 
      for aromatic residues, which was increased in DP2K69 and extended to arginine. 
      Finally, we used the experimental data to determine the best molecular-modeling 
      approach for assessing aminoacid selectivity of the two pockets. The results with 
      best predictive value were obtained when single aminoacids were evaluated inside 
      each single pocket, thus, reducing the influence of the overall peptide/ major 
      histocompatibility complex interaction. In conclusion, the HLA-DPbeta69 
      polymorphism plays a fundamental role in the peptide-binding selectivity of 
      HLA-DP. Furthermore, as this polymorphism is the main change in the pocket 4 area 
      of HLA-DP, it could represent a supertype among HLA-DP molecules significantly 
      contributing to the selection of epitopes presented in the context of this HLA 
      isotype.
FAU - Berretta, F
AU  - Berretta F
AD  - Department of Internal Medicine, University of Tor Vergata, Rome, Italy.
FAU - Butler, R H
AU  - Butler RH
FAU - Diaz, G
AU  - Diaz G
FAU - Sanarico, N
AU  - Sanarico N
FAU - Arroyo, J
AU  - Arroyo J
FAU - Fraziano, M
AU  - Fraziano M
FAU - Aichinger, G
AU  - Aichinger G
FAU - Wucherpfennig, K W
AU  - Wucherpfennig KW
FAU - Colizzi, V
AU  - Colizzi V
FAU - Saltini, C
AU  - Saltini C
FAU - Amicosante, M
AU  - Amicosante M
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PT  - Research Support, U.S. Gov't, Non-P.H.S.
PL  - England
TA  - Tissue Antigens
JT  - Tissue antigens
JID - 0331072
RN  - 0 (HLA-DP Antigens)
RN  - 0 (Peptides)
RN  - 0 (Recombinant Proteins)
RN  - 3KX376GY7L (Glutamic Acid)
RN  - K3Z4F929H6 (Lysine)
SB  - IM
MH  - Amino Acid Sequence
MH  - Amino Acid Substitution
MH  - Animals
MH  - Binding Sites
MH  - Cell Line, Tumor
MH  - Glutamic Acid/genetics
MH  - HLA-DP Antigens/*genetics/metabolism
MH  - Humans
MH  - Hydrogen-Ion Concentration
MH  - Lysine/genetics
MH  - Models, Molecular
MH  - Molecular Sequence Data
MH  - Mutation
MH  - Peptides/genetics/metabolism
MH  - *Polymorphism, Genetic
MH  - Protein Binding
MH  - Recombinant Proteins/genetics/metabolism
EDAT- 2003/11/18 05:00
MHDA- 2004/07/23 05:00
CRDT- 2003/11/18 05:00
PHST- 2003/11/18 05:00 [pubmed]
PHST- 2004/07/23 05:00 [medline]
PHST- 2003/11/18 05:00 [entrez]
AID - 131 [pii]
AID - 10.1046/j.1399-0039.2003.00131.x [doi]
PST - ppublish
SO  - Tissue Antigens. 2003 Dec;62(6):459-71. doi: 10.1046/j.1399-0039.2003.00131.x.