Allelic variation in key peptide-binding pockets discriminates between closely related diabetes-protective and diabetes-susceptible HLA-DQB1*06 alleles
Φόρτωση...
Ημερομηνία
Συγγραφείς
Ettinger, R. A.
Papadopoulos, G. K.
Moustakas, A. K.
Nepom, G. T.
Kwok, W. W.
Τίτλος Εφημερίδας
Περιοδικό ISSN
Τίτλος τόμου
Εκδότης
Περίληψη
Τύπος
Είδος δημοσίευσης σε συνέδριο
Είδος περιοδικού
peer-reviewed
Είδος εκπαιδευτικού υλικού
Όνομα συνεδρίου
Όνομα περιοδικού
J Immunol
Όνομα βιβλίου
Σειρά βιβλίου
Έκδοση βιβλίου
Συμπληρωματικός/δευτερεύων τίτλος
Περιγραφή
HLA-DQA1*0102-DQB1*0602 is associated with protection against type 1 diabetes (T1D). A similar allele, HLA-DQA1*0102-DQB1*0604, contributes to T1D susceptibility in certain populations but differs only at seven amino acids from HLA-DQA1*0102-DQB1*0602. Five of these polymorphisms are found within the peptide-binding groove, suggesting that differences in peptide binding contribute to the mechanism of their association with T1D. In this study, we determine the peptide-binding motif for HLA-DQA1*0102-DQB1*0604 allelic protein (DQ0604) in comparison to the established HLA-DQA1*0102-DQB1*0602 (DQ0602) motif using binding assays with model peptides from T1D autoantigens and homology modeling using the coordinates of the DQ0602-hypocretin 1-13 crystal structure. The peptide binding preferences were deduced with a peptide from insulin that bound both with a 2- to 3-fold difference in avidity using the same amino acids in the peptide as anchors. Peptide binding differences directly influenced by the polymorphisms in or nearby pockets 1, 6, and 9 were observed. In pocket 1, DQ0604 was better able to accommodate aromatic residues due to the beta86 and beta87 polymorphisms. A negatively charged amino acid was preferred by DQ0604 in pocket 6 due to the positively charged beta30His. In pocket 9, DQ0604 preferred aromatic amino acids due to the beta9 and beta30 polymorphisms and had low tolerance of acidic residues. beta57Val in DQ0604 functions differently than beta57Ala, in that it pushes alpha76Arg outside of the pocket, preventing the formation of a salt bridge with an acidic amino acid in the peptide. This study furthers our understanding of the structure-function relationships of MHC class II polymorphisms.
Περιγραφή
Λέξεις-κλειδιά
*Alleles, Amino Acid Motifs, Autoantigens/metabolism, Binding Sites/genetics/immunology, Biotin/analogs & derivatives/metabolism, Cell Line, Transformed, Diabetes Mellitus, Type 1/*genetics/*immunology, *Genetic Predisposition to Disease, Genetic Variation, Glutamate Decarboxylase/metabolism, HLA-DQ Antigens/*genetics/metabolism, HLA-DQ beta-Chains, Humans, Insulin/analogs & derivatives/metabolism, Isoenzymes/metabolism, Membrane Glycoproteins/*genetics/metabolism, Membrane Proteins/metabolism, Models, Molecular, Peptide Fragments/*genetics/*metabolism, Proinsulin/metabolism, Protein Binding/genetics/immunology, Protein Structure, Tertiary, Protein Tyrosine Phosphatase, Non-Receptor Type 1, Protein Tyrosine Phosphatases/metabolism, Receptor-Like Protein Tyrosine Phosphatases, Class 8
Θεματική κατηγορία
Παραπομπή
Σύνδεσμος
http://www.ncbi.nlm.nih.gov/pubmed/16424231
http://www.jimmunol.org/content/176/3/1988.full.pdf
http://www.jimmunol.org/content/176/3/1988.full.pdf
Γλώσσα
en
Εκδίδον τμήμα/τομέας
Όνομα επιβλέποντος
Εξεταστική επιτροπή
Γενική Περιγραφή / Σχόλια
Ίδρυμα και Σχολή/Τμήμα του υποβάλλοντος
Πανεπιστήμιο Ιωαννίνων. Σχολή Επιστημών Υγείας. Τμήμα Ιατρικής