title: Negatively-charged amino acids at the peptide-binding pocket of HLA-DPB1 alleles are associated with susceptibility to anti-topoisomerase I-positive systemic sclerosis.
abstract: We investigated shared characteristics of amino acid sequences in the at risk HLA-DPB1 alleles in systemic sclerosis (SSc). Amino acid sequences and their structural features of HLA-DP molecules in 127 Korean SSc patients and 548 healthy Korean controls were analyzed with a focus on known HLA-DP binding motifs. The binding grooves containing more negatively-charged triplets (NCT) had higher odds ratios of anti-topoisomerase I antibody (ATA)-positive SSc. In particular, the co-existence of a NCT at position 82-85 and more than one additional NCT were critical for increased risk of ATA-positive SSc. Molecular dynamic simulations showed that the model peptide with positive charge from topoisomerase I fits more closely into HLA-DP alleles possessing more NCTs. ATA-positive SSc patients share NCTs at the peptide-binding groove of HLA-DPB1 molecules.
authors.affiliation: Division of Rheumatology, Department of Internal Medicine, Seoul National University College of Medicine, Seoul, Republic of Korea.
authors.forename: Jeong Seok
authors.initials: JS
authors.lastname: Lee
authors.affiliation: Division of Rheumatology, Department of Internal Medicine, Seoul National University College of Medicine, Seoul, Republic of Korea.
authors.forename: Jin Kyun
authors.initials: JK
authors.lastname: Park
authors.affiliation: Dong-A Pharmaceutical Co, Seoul, Republic of Korea.
authors.forename: Heung Jae
authors.initials: HJ
authors.lastname: Kim
authors.affiliation: Dong-A Pharmaceutical Co, Seoul, Republic of Korea.
authors.forename: Hyung Ki
authors.initials: HK
authors.lastname: Lee
authors.affiliation: Division of Rheumatology, Department of Internal Medicine, Seoul National University College of Medicine, Seoul, Republic of Korea.
authors.forename: Yeong Wook
authors.initials: YW
authors.lastname: Song
authors.affiliation: Division of Rheumatology, Department of Internal Medicine, Seoul National University College of Medicine, Seoul, Republic of Korea. Electronic address: leb7616@snu.ac.kr.
authors.forename: Eun Bong
authors.initials: EB
authors.lastname: Lee
mesh_terms: D020816:Amino Acid Motifs / Q000235:genetics; D000596:Amino Acids / Q000235:genetics*; D001323:Autoantibodies / Q000097:blood; D003198:Computer Simulation; D004264:DNA Topoisomerases, Type I / Q000276:immunology; D000939:Epitopes / Q000378:metabolism; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease; D059868:HLA-DP beta-Chains / Q000235:genetics*; D006801:Humans; D007723:Korea; D010446:Peptide Fragments / Q000378:metabolism; D011110:Polymorphism, Genetic; D011485:Protein Binding; D012306:Risk; D012595:Scleroderma, Systemic / Q000235:genetics*; D013329:Structure-Activity Relationship
chemical_list: D000596:Amino Acids; D001323:Autoantibodies; D000939:Epitopes; D059868:HLA-DP beta-Chains; C071170:HLA-DPB1 antigen; D010446:Peptide Fragments; D004264:DNA Topoisomerases, Type I
keywords: Epitope; HLA; Systemic sclerosis; Topoisomerase I