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. 2011 Jun;53(6):1967-76.
doi: 10.1002/hep.24299. Epub 2011 May 13.

Electrostatic modifications of the human leukocyte antigen-DR P9 peptide-binding pocket and susceptibility to primary sclerosing cholangitis

Johannes R Hov  1 , Vasilis Kosmoliaptsis, James A Traherne, Marita Olsson, Kirsten M Boberg, Annika Bergquist, Erik Schrumpf, J Andrew Bradley, Craig J Taylor, Benedicte A Lie, John Trowsdale, Tom H Karlsen
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Free PMC article

Electrostatic modifications of the human leukocyte antigen-DR P9 peptide-binding pocket and susceptibility to primary sclerosing cholangitis

Johannes R Hov et al. Hepatology. 2011 Jun.
Free PMC article

Abstract

The strongest genetic risk factors for primary sclerosing cholangitis (PSC) are found in the human leukocyte antigen (HLA) complex at chromosome 6p21. Genes in the HLA class II region encode molecules that present antigen to T lymphocytes. Polymorphisms in these genes are associated with most autoimmune diseases, most likely because they contribute to the specificity of immune responses. The aim of this study was to analyze the structure and electrostatic properties of the peptide-binding groove of HLA-DR in relation to PSC. Thus, four-digit resolution HLA-DRB1 genotyping was performed in 356 PSC patients and 366 healthy controls. Sequence information was used to assign which amino acids were encoded at all polymorphic positions. In stepwise logistic regressions, variations at residues 37 and 86 were independently associated with PSC (P = 1.2 × 10(-32) and P = 1.8 × 10(-22) in single-residue models, respectively). Three-dimensional modeling was performed to explore the effect of these key residues on the HLA-DR molecule. This analysis indicated that residue 37 was a major determinant of the electrostatic properties of pocket P9 of the peptide-binding groove. Asparagine at residue 37, which was associated with PSC, induced a positive charge in pocket P9. Tyrosine, which protected against PSC, induced a negative charge in this pocket. Consistent with the statistical observations, variation at residue 86 also indirectly influenced the electrostatic properties of this pocket. DRB1*13:01, which was PSC-associated, had a positive P9 pocket and DRB1*13:02, protective against PSC, had a negative P9 pocket.

Conclusion: The results suggest that in patients with PSC, residues 37 and 86 of the HLA-DRβ chain critically influence the electrostatic properties of pocket P9 and thereby the range of peptides presented.

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Figures

Fig. 1
Fig. 1
Structure and molecular surface electrostatic potential of pocket P9. (A) The structure and electrostatic potential of HLA-DRB1*03:01. The area within the frame is depicted in expanded form in (B,C). All structures were superimposed on HLA-DRB1*03:01 and therefore show the same view. HLA-DR carrying the risk residue Asn37 in the β chain had P9 pockets (arrows) with positive charge (B), whereas molecules expressing Tyr37 had P9 pockets (arrows) with consistently negative charge (C). Potentials less than −5 kT/e are colored red, those greater than 5 kT/e blue, and neutral potentials (0 kT/e) are colored white. Linear interpolation was used to produce the color for surface potentials between these values.
Fig. 2
Fig. 2
Structure and molecular surface electrostatic potential of pocket P1. (A) The structure and electrostatic potential of HLA-DRB1*03:01. The area within the frame is depicted in expanded form in (B). All structures were superimposed on HLA-DRB1*03:01 and therefore show the same view. Structural modeling and calculation of the electrostatic potential at the P1 pocket (arrows) of representative HLA-DR molecules showed that the Gly/Val dimorphism at position 86 had a minimal physiochemical effect (B). The majority of HLA-DR molecules examined had P1 pockets with an overall neutral charge. HLA-DRB1*03:01 and -DRB1*14:01 express Val86 whereas -DRB1*01:01 and -DRB1*04:01 express Gly86. Potentials less than −5 kT/e are colored red, those greater than 5 kT/e blue, and neutral potentials (0 kT/e) are colored white. Linear interpolation was used to produce the color for surface potentials between these values.
Fig. 3
Fig. 3
Electrostatic modification of pocket P9 by the Gly86-to-Val86 substitution. The structure and electrostatic potential of the peptide-binding groove is shown for (structures were superimposed) HLA-DRB1*13:01 (left figures) and -DRB1*13:02 (right figures); these molecules have a single amino acid sequence difference at position 86 (Val86 and Gly86, respectively). HLA-DRB1*13:02 has an electronegative pocket P9 despite the presence of Asn at position 37, suggesting a long-range effect of the Val86-to-Gly86 substitution. The molecular surface is colored according to the calculated electrostatic potential, as for Figs. 1 and 2.
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References

    1. Bergquist A, Montgomery SM, Bahmanyar S, Olsson R, Danielsson A, Lindgren S, et al. Increased risk of primary sclerosing cholangitis and ulcerative colitis in first-degree relatives of patients with primary sclerosing cholangitis. Clin Gastroenterol Hepatol. 2008;6:939–943. - PubMed
    1. Karlsen TH, Franke A, Melum E, Kaser A, Hov JR, Balschun T, et al. Genome-wide association analysis in primary sclerosing cholangitis. Gastroenterology. 2010;138:1102–1111. - PubMed
    1. Donaldson PT, Norris S. Evaluation of the role of MHC class II alleles, haplotypes and selected amino acid sequences in primary sclerosing cholangitis. Autoimmunity. 2002;35:555–564. - PubMed
    1. Spurkland A, Saarinen S, Boberg KM, Mitchell S, Broome U, Caballeria L, et al. HLA class II haplotypes in primary sclerosing cholangitis patients from five European populations. Tissue Antigens. 1999;53:459–469. - PubMed
    1. Schrumpf E, Fausa O, Forre O, Dobloug JH, Ritland S, Thorsby E. HLA antigens and immunoregulatory T cells in ulcerative colitis associated with hepatobiliary disease. Scand J Gastroenterol. 1982;17:187–191. - PubMed

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