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PMID: 14769912 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't

Crystal structure of HLA-DQ0602 that protects against type 1 diabetes and confers strong susceptibility to narcolepsy.

Proceedings of the National Academy of Sciences of the United States of America ·Vol. 101 ·No. 7 ·2004-02-17 ·Pages 1999-2004

Siebold C, Hansen BE, Wyer JR, Harlos K, Esnouf RE, Svejgaard A, Bell JI, Strominger JL, Jones EY, Fugger L

Abstract

The MHC class II molecule DQ0602 confers strong susceptibility to narcolepsy but dominant protection against type 1 diabetes. The crystal structure of DQ0602 reveals the molecular features underlying these contrasting genetic properties. Structural comparisons to homologous DQ molecules with differential disease associations highlight a previously unrecognized interplay between the volume of the P6 pocket and the specificity of the P9 pocket, which implies that presentation of an expanded peptide repertoire is critical for dominant protection against type 1 diabetes. In narcolepsy, the volume of the P4 pocket appears central to the susceptibility, suggesting that the presentation of a specific peptide population plays a major role.

MeSH Terms
Alleles Amino Acid Sequence Binding Sites Crystallography, X-Ray Diabetes Mellitus, Type 1/genetics Genetic Predisposition to Disease HLA-DQ Antigens/chemistry,genetics HLA-DQ beta-Chains Humans Membrane Glycoproteins Models, Molecular Narcolepsy/genetics Polymorphism, Genetic/genetics Protein Binding Protein Conformation Structure-Activity Relationship
Chemicals
HLA-DQ Antigens HLA-DQ beta-Chains HLA-DQB1 antigen Membrane Glycoproteins
Authors & Affiliations
10 authors, click to expand affiliations / ORCID
Siebold Christian
Division of Structural Biology, The Henry Wellcome Building for Genomic Medicine, University of Oxford, Roosevelt Drive, Oxford OX3 7BN, United Kingdom.
Hansen Bjarke E
Wyer Jessica R
Harlos Karl
Esnouf Robert E
Svejgaard Arne
Bell John I
Strominger Jack L
Jones E Yvonne
Fugger Lars
References (36)
36 references, click to expand
  1. Rapid automated molecular replacement by evolutionary search.
    Acta Crystallogr D Biol Crystallogr. 1999 Feb;55(Pt 2):484-91 PMID: 10089360
  2. The sleep disorder canine narcolepsy is caused by a mutation in the hypocretin (orexin) receptor 2 gene.
    Cell. 1999 Aug 6;98(3):365-76 PMID: 10458611
  3. Narcolepsy in orexin knockout mice: molecular genetics of sleep regulation.
    Cell. 1999 Aug 20;98(4):437-51 PMID: 10481909
  4. Regulatory T cells: key controllers of immunologic self-tolerance.
    Cell. 2000 May 26;101(5):455-8 PMID: 10850488
  5. Structural basis of peptide binding and presentation by the type I diabetes-associated MHC class II molecule of NOD mice.
    Immunity. 2000 Jun;12(6):699-710 PMID: 10894169
  6. A mutation in a case of early onset narcolepsy and a generalized absence of hypocretin peptides in human narcoleptic brains.
    Nat Med. 2000 Sep;6(9):991-7 PMID: 10973318
  7. Thymic selection of CD4+CD25+ regulatory T cells induced by an agonist self-peptide.
    Nat Immunol. 2001 Apr;2(4):301-6 PMID: 11276200
  8. Structure of a human insulin peptide-HLA-DQ8 complex and susceptibility to type 1 diabetes.
    Nat Immunol. 2001 Jun;2(6):501-7 PMID: 11376336
  9. Genetic ablation of orexin neurons in mice results in narcolepsy, hypophagia, and obesity.
    Neuron. 2001 May;30(2):345-54 PMID: 11394998
  10. Narcolepsy: clinical features, new pathophysiologic insights, and future perspectives.
    J Clin Neurophysiol. 2001 Mar;18(2):78-105 PMID: 11435802
  11. Genetic protection from the inflammatory disease type 1 diabetes in humans and animal models.
    Immunity. 2001 Sep;15(3):387-95 PMID: 11567629
  12. CSF hypocretin/orexin levels in narcolepsy and other neurological conditions.
    Neurology. 2001 Dec 26;57(12):2253-8 PMID: 11756606
  13. The role of hypocretins (orexins) in sleep regulation and narcolepsy.
    Annu Rev Neurosci. 2002;25:283-313 PMID: 12052911
  14. DQ (rather than DR) gene marks susceptibility to narcolepsy.
    Lancet. 1992 Apr 25;339(8800):1052 PMID: 1349071
  15. Improved methods for building protein models in electron density maps and the location of errors in these models.
    Acta Crystallogr A. 1991 Mar 1;47 ( Pt 2):110-9 PMID: 2025413
  16. Narcolepsy.
    N Engl J Med. 1990 Aug 9;323(6):389-94 PMID: 2196464
  17. Analysis of HLA-DQ genotypes and susceptibility in insulin-dependent diabetes mellitus.
    N Engl J Med. 1990 Jun 28;322(26):1836-41 PMID: 2348836
  18. Processing of X-ray diffraction data collected in oscillation mode.
    Methods Enzymol. 1997;276:307-26 PMID: 27754618
  19. HLA-DQ beta gene contributes to susceptibility and resistance to insulin-dependent diabetes mellitus.
    Nature. 1987 Oct 15-21;329(6140):599-604 PMID: 3309680
  20. Crystal structure of cat muscle pyruvate kinase at a resolution of 2.6 A.
    J Mol Biol. 1979 Oct 15;134(1):109-42 PMID: 537059
  21. The structure of an intermediate in class II MHC maturation: CLIP bound to HLA-DR3.
    Nature. 1995 Nov 30;378(6556):457-62 PMID: 7477400
  22. Narcolepsy and immunity.
    Adv Neuroimmunol. 1995;5(1):23-37 PMID: 7795891
  23. Production of soluble MHC class II proteins with covalently bound single peptides.
    Nature. 1994 May 12;369(6476):151-4 PMID: 8177320
  24. Autoimmune hypothesis in narcolepsy.
    Neurophysiol Clin. 1993 Jan;23(1):15-22 PMID: 8446070
  25. Insulin-dependent diabetes mellitus.
    Cell. 1996 May 3;85(3):291-7 PMID: 8616883
  26. Errors in protein structures.
    Nature. 1996 May 23;381(6580):272 PMID: 8692262
  27. Expression of recombinant HLA-DR2 molecules. Replacement of the hydrophobic transmembrane region by a leucine zipper dimerization motif allows the assembly and secretion of soluble DR alpha beta heterodimers.
    J Biol Chem. 1996 Aug 16;271(33):20156-62 PMID: 8702739
  28. Limited loss of tolerance to islet autoantigens in ICA+ first degree relatives of patients with type I diabetes expressing the HLA dqb1*0602 allele.
    J Autoimmun. 1996 Jun;9(3):423-5 PMID: 8816981
  29. Antiislet autoantibodies usually develop sequentially rather than simultaneously.
    J Clin Endocrinol Metab. 1996 Dec;81(12):4264-7 PMID: 8954025
  30. HLA DR15 (DR2) and DQB1*0602 typing studies in 188 narcoleptic patients with cataplexy.
    Neurology. 1997 Jun;48(6):1550-6 PMID: 9191765
  31. A mechanism for the major histocompatibility complex-linked resistance to autoimmunity.
    J Exp Med. 1997 Oct 6;186(7):1059-75 PMID: 9314555
  32. Major histocompatibility complex class II molecules can protect from diabetes by positively selecting T cells with additional specificities.
    J Exp Med. 1998 Feb 2;187(3):379-87 PMID: 9449718
  33. A peptide binding motif for HLA-DQA1*0102/DQB1*0602, the class II MHC molecule associated with dominant protection in insulin-dependent diabetes mellitus.
    J Immunol. 1998 Mar 1;160(5):2365-73 PMID: 9498778
  34. Functional characterization of HLA-DRA1*0101/DRB1*0401 molecules expressed in Drosophila melanogaster cells.
    Tissue Antigens. 1998 Feb;51(2):119-28 PMID: 9510368
  35. Crystallography & NMR system: A new software suite for macromolecular structure determination.
    Acta Crystallogr D Biol Crystallogr. 1998 Sep 1;54(Pt 5):905-21 PMID: 9757107
  36. Exceptional stability of the HLA-DQA1*0102/DQB1*0602 alpha beta protein dimer, the class II MHC molecule associated with protection from insulin-dependent diabetes mellitus.
    J Immunol. 1998 Dec 1;161(11):6439-45 PMID: 9834137
Article Info
Journal
Proceedings of the National Academy of Sciences of the United States of America
Abbr.
Proc Natl Acad Sci U S A
ISSN
0027-8424
DOI
10.1073/pnas.0308458100
Published
2004-02-17
Epub
2004-00-09
Pages
1999-2004
Language
English
Region
United States
NLM ID
7505876
PMCID
PMC357041
Subset
IM
Databases
PDB
1UVQ
External Links
PubMed source DOI: 10.1073/pnas.0308458100 PMC Full Text View journal details
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