BINDING OF PEPTIDES NATURALLY PRESENTED BY HLA-B27 TO THE DIFFERENTIALLY DISEASE-ASSOCIATED B-ASTERISK-2704 AND B-ASTERISK-2706 SUBTYPES, AND TO MUTANTS MIMICKING THEIR POLYMORPHISM

B2704 and B*2706 are closely related HLA-B27 subtypes of which the fo rmer but not the latter is associated to ankylosing spondylitis. Their peptide specificity relative to other disease-associated subtypes was analyzed by testing binding of self-peptides naturally presented by B 2705 or B*2702, and synthetic analogs, to B*2704, B*2706, and site-sp ecific mutants mimicking their changes. Peptides with basic, aliphatic or aromatic C-terminal residues bound to B2705 with similar affinity . In B2704 C-terminal aliphatic/aromatic residues were preferred. B*2 706 discriminated drastically between polar and nonpolar C-terminal re sidues, showing strong preference for Leu and Phe, and less than B270 4 for basic and Tyr residues. Loss of single acidic charges (D>S77, D> Y116) increased preference for C-terminal Leu and Phe, but allowed eff icient binding of peptides with basic residues or Tyr. Their gain (V>E 152, H>D114) maintained wide C-terminal specificity, but severely impa ired binding, presumably by disrupting interactions with internal pept ide residues. This was compensated by Y116 in the double D114Y116 muta nt. The specificity of B2704 and B*2706 was explained only partially by the separate effects of single mutations, indicating that novel pro perties arise from concomitant changes at various positions. For insta nce, specificity of B2706 for nonpolar C-terminal residues required s imultaneous removal of Asp77 and Asp116. B2706 differed from B*2705, B2702, and B*2704 in its lower suitability for C-terminal Tyr, sugges ting that this feature might be relevant for HLA-B27 association to sp ondyloarthropathy.