Human Class I histocompatibility (mAb TP25.99) antigen-peptide complexes

Induced Peptide Conformation in the Presence of mAb TP25.99

Human Class I histocompatibility antigen-peptide complexes initiate the cascade that results in the rejection of foreign tissue transplants. T cell receptor molecules bind the a1 and a2 domains of the HLA heavy chain in the antigen-peptide complex while the CD8 co-receptor binds the a3 domain to initiate a response. The anti-HLA Class I monoclonal antibody (mAb) TP25.99 has an unusual specificity as it recognizes determinants expressed on b2-m associated and b2-m free HLA Class I heavy chains. In the companion paper using phage display peptide libraries (Desai et al., 1998) we reported the identification of a cyclic and a linear peptide reacting with mAb TP25.99. The nineteen residue linear synthetic peptide sequence (X19) contains a stretch homologous to residues 239-242, 245 and 246 of HLA Class I heavy chains. The twelve residue cyclic peptide (LX-8) contains a stretch homologous to residues 194-198 of HLA Class I heavy chains. Analysis by two-dimensional transfer NOE spectroscopy of the induced solution structure of the X19 and LX-8 peptides in the presence of mAb TP25.99 showed that in spite of the lack of sequence homology, the two peptides adopt a similar structural motif. This motif corresponds to a short helical segment followed by a tight turn, reminiscent of the determinant loop region (residues 194-198) on b2-m associated HLA Class I heavy chains. An atomic rms distribution between the backbone atoms of X19 (residues 4-11) and LX-8 (residues 10-3) is 1.06 A°. The structural similarity between the X19 and LX-8 peptides and the lack of sequence homology suggests that mAb TP25.99 predominantly recognizes a structural motif instead of a consensus sequence. These results are also consistent with the observation that the association of HLA Class I heavy chains with b2-m modifies drastically their conformation and causes a change in their antigenic profile.

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