The binding of antigenic peptides to HLA-DR is influenced by interactions between pocket 6 and pocket 9.
Peptide binding to class II MHC protein is commonly viewed as a combination of discrete anchor residue preferences for pockets 1, 4, 6/7, and 9. However, previous studies have suggested cooperative effects during the peptide binding process. Investigation of the DRB1*0901 binding motif demonstrated a clear interaction between peptide binding pockets 6 and 9. In agreement with prior studies, pockets 1 and 4 exhibited clear binding preferences. Previously uncharacterized pockets 6 and 7 accommodated a wide variety of residues. However, although it was previously reported that pocket 9 is completely permissive, several substitutions at this position were unable to bind. Structural modeling revealed a probable interaction between pockets 6 and 9 through beta9Lys. Additional binding studies with doubly substituted peptides confirmed that the amino acid bound within pocket 6 profoundly influences the binding preferences for pocket 9 of DRB1*0901, causing complete permissiveness of pocket 9 when a small polar residue is anchored in pocket 6 but accepting relatively few residues when a basic residue is anchored in pocket 6. The beta9Lys residue is unique to DR9 alleles. However, similar studies with doubly substituted peptides confirmed an analogous interaction effect for DRA1/B1*0301, a beta9Glu allele. Accounting for this interaction resulted in improved epitope prediction. These findings provide a structural explanation for observations that an amino acid in one pocket can influence binding elsewhere in the MHC class II peptide binding groove.
James
Eddie A
EA
Benaroya Research Institute at Virginia Mason, Seattle, WA 98101, USA.
Moustakas
Antonis K
AK
Bui
John
J
Nouv
Randi
R
Papadopoulos
George K
GK
Kwok
William W
WW
D020816:Amino Acid Motifs / Q000276:immunology; D019943:Amino Acid Substitution / Q000276:immunology; D001667:Binding, Competitive / Q000276:immunology; D018984:Epitopes, T-Lymphocyte / Q000378:metabolism; D006684:HLA-DR Antigens / Q000737:chemistry / Q000276:immunology / Q000378:metabolism*; D059810:HLA-DR Serological Subtypes; D059805:HLA-DR alpha-Chains; D015803:HLA-DR3 Antigen / Q000737:chemistry / Q000276:immunology / Q000378:metabolism*; D059811:HLA-DRB1 Chains; D006801:Humans; D010455:Peptides / Q000737:chemistry / Q000276:immunology / Q000378:metabolism*; D011485:Protein Binding / Q000276:immunology; D013601:T-Lymphocytes / Q000276:immunology / Q000378:metabolism
D018984:Epitopes, T-Lymphocyte; D006684:HLA-DR Antigens; D059810:HLA-DR Serological Subtypes; D059805:HLA-DR alpha-Chains; D015803:HLA-DR3 Antigen; C038988:HLA-DR9 antigen; D059811:HLA-DRB1 Chains; D010455:Peptides