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Complexes of Two Cohorts of CLIP Peptides and HLA-DQ2 of the Autoimmune DR3-DQ2 Haplotype Are Poor Substrates for HLA-DM¹

Lars-Egil Fallang^*, Sujin Roh, Anders Holm^*, Elin Bergseng, Taejin Yoon, Burkhard Fleckenstein^*, Arunima Bandyopadhyay, Elizabeth D. Mellins^2,3, and Ludvig M. Sollid^2,3,*,

^* Centre for Immune Regulation and Institute of Immunology, University of Oslo, Oslo, Norway; Centre for Immune Regulation and Institute of Immunology, University Hospital, Oslo, Norway; and Department of Pediatrics, Stanford University, Stanford, CA 94305

Atypical invariant chain (Ii) CLIP fragments (CLIP2) have been found in association with HLA-DQ2 (DQ2) purified from cell lysates. We mapped the binding register of CLIP2 (Ii 96–104) to DQ2 and found proline at the P1 position, in contrast to the canonical CLIP1 (Ii 83–101) register with methionine at P1. CLIP1/2 peptides are the predominant peptide species, even for DQ2 from HLA-DM (DM)-expressing cells. We hypothesized that DQ2-CLIP1/2 might be poor substrates for DM. We measured DM-mediated exchange of CLIP and other peptides for high-affinity indicator peptides and found it is inefficient for DQ2. DM-DQ-binding and DM chaperone effects on conformation and levels of DQ are also reduced for DQ2, compared with DQ1. We suggest that the unusual interaction of DQ2 with Ii and DM may provide a basis for the known disease associations of DQ2.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by grants from the Research Council of Norway, the National Institutes of Health (U19 AI02042 to E.D.M.), the Wasie Foundation (to E.D.M.). and the Norwegian Foundation for Health and Rehabilitation.

² E.D.M. and L.M.S. made equivalent contributions.

³ Address correspondence and reprint requests to Dr. Elizabeth D. Mellins, Department of Pediatrics, Stanford University, Stanford, CA 94305 and Dr. Ludvig M. Sollid, Institute of Immunology, Rikshospitalet, 0027 Oslo, Norway. E-mail addresses: mellins{at}stanford.edu and l.m.sollid{at}medisin.uio.no

⁴ Abbreviations used in this paper: Ii, invariant chain; ACN, acetonitrile; B-LCL, B lymphoblastoid cell line; s, soluble; TFA, trifluoroacetic acid; MFI, mean fluorescence intensity; MS, mass spectrometry; ICPL, isotope coded peptide labeling; LC, liquid chromatography.