Antigenic peptide molecular recognition by the DRB1-DQB1 haplotype modulates multiple sclerosis susceptibility.
Multiple sclerosis (MS) is an autoimmune disease of the central nervous system that has a notably high incidence in Sardinia. Our study focuses on two HLA class II haplotypes associated with the disease in Sardinia, the rare predisposing DRB1*15:01-DQB1*06:02 and the widespread protective DRB1*16:01-DQB1*05:02. This framework enabled the highlighting of HLA binding pocket specificity and peptide recognition mechanisms by employing molecular dynamics simulations of the whole DRB1-DQB1 haplotype interacting with MBP- and EBV-derived peptides. We analyzed peptide-protein interaction networks and temporal evolution of the original complexes and after key amino acid mutations. The mutation G86V of the protective DRB1 allele exerted its effect mainly in the presence of the EBV viral peptide, with local and long range outcomes. However, the V38A mutation of the protective DQB1 showed a long range effect only in the case of the MBP myelin peptide. Our findings also demonstrate a DRB1/DQB1 complementary molecular recognition of peptides. This mechanism could provide a robust synergistic action and a differential role of DRB1 and DQB1 in tissues and in the time-steps towards autoimmunity. In addition, we demonstrate that negatively charged residues in pockets 4 and 9 play a role in MS susceptibility. Our findings are supported by recent experiments using a closely related MS animal model. Overall, our analysis confirms the role of the DRB1-DQB1 haplotype in conferring disease predisposition and could provide a valuable aid in designing optimal therapeutic peptides for MS therapy.
CRS4 Biomedicine, Science and Technology Park, Piscinamanna, Pula, Italy. akumar@crs4.it ep@crs4.it.
Amit
A
Kumar
Paola
P
Melis
Vito
V
Genna
Eleonora
E
Cocco
Maria Giovanna
MG
Marrosu
Enrico
E
Pieroni
D000596:Amino Acids; D001665:Binding Sites; D020022:Genetic Predisposition to Disease; D059866:HLA-DQ beta-Chains / Q000737:chemistry / Q000378:metabolism*; D059811:HLA-DRB1 Chains / Q000737:chemistry / Q000378:metabolism*; D006239:Haplotypes; D006801:Humans; D007558:Italy; D008958:Models, Molecular; D009103:Multiple Sclerosis / Q000235:genetics* / Q000473:pathology; D009154:Mutation; D010455:Peptides / Q000378:metabolism*; D011487:Protein Conformation
D000596:Amino Acids; D059866:HLA-DQ beta-Chains; C069051:HLA-DQB1 antigen; D059811:HLA-DRB1 Chains; C489631:HLA-DRB1*15:01 antigen; D010455:Peptides