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Presentation of Cytosolically Stable Peptides by HLA-B27 Is Not Dependent on the Canonic Interactions of N-Terminal Basic Residues in the A Pocket¹

Centro de Biología Molecular "Severo Ochoa" (Consejo Superior de Investigaciones Científicas and Universidad Autónoma de Madrid), Universidad Autónoma, Madrid, Spain

HLA-B27 binds peptides with R at position 2. Additionally, a substantial fraction of the HLA-B27-bound peptide repertoire has basic residues at position 1. It is unclear whether this is determined by structural complementarity with the A pocket of the peptide-binding site, by the increased availability of peptides with dibasic N-terminal sequences resulting from their cytosolic stability, or both. To distinguish between these possibilities two B*2705 mutants were generated in which one or two A pocket surface residues stabilizing the peptidic R1 side chain were changed: E163T and E163T-W167S. Both mutants bound a large fraction of the constitutive peptide repertoire of B*2705. Moreover, 90 B*2705 ligands of known sequence were examined for their endogenous presentation by the mutants. The E163T mutation alone had a limited effect on binding of peptides with R1 or K1 and on the relative frequencies of N-terminal residues. However, it decreased the overall stability of the molecule. The E163T-W167S mutant also bound many of the B*2705 ligands with N-terminal basic residues, but its preference for G1 was significantly decreased. The results indicate that the capacity of HLA-B27 to bind peptides with N-terminal basic residues is largely independent of the canonic interactions that stabilize at least the R1 side chain. Thus, the prevalence of HLA-B27 ligands with dibasic N-terminal sequences may be significantly influenced by the increased availability of these peptides resulting from their cytosolic stability. This confers to HLA-B27 a unique capacity to present Ags generated in low amounts, but resistant to intracellular degradation.

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 Grant SAF2005/03188 from the Ministry of Science and Technology and an institutional grant from the Fundación Ramón Areces to the Centro de Biología Molecular "Severo Ochoa".

² Address correspondence and reprint requests to Dr. José A. López de Castro, Centro de Biología Molecular "Severo Ochoa", C/Nicolás Cabrera, N.1, Universidad Autónoma, 28049 Madrid, Spain. E-mail address: aldecastro{at}cbm.uam.es

³ Abbreviations used in this paper: P, position: P1, N terminal position; T163, E163T; T163S167, E163T-W167S; C1R, HMy2.C1R; HC, heavy chain; TFA, trifluoroacetic acid; MS, mass spectrometry; m/z, mass-to-charge.