During assembly, HLA class II molecules associate with the
invariant chain. As the result, the
peptide-binding groove is occupied by an
invariant chain peptide termed
CLIP (
class-II-associated invariant chain peptide; sequence MRMATPLLM). By mass spectrometry, we have now characterized
peptides that are naturally present in HLA-DQ2. This analysis revealed that 22 variants of Ii-derived
peptides are associated with HLA-DQ2. Strikingly, the large majority of those do not contain the conventional
CLIP sequence MRMATPLLM, but instead a
peptide that partially overlaps with
CLIP, sequence TPLLMQALPM.
Peptide binding studies indicate that this alternative
CLIP peptide has superior HLA-DQ2 binding properties compared to the conventional
CLIP and that the minimal nine-
amino-acid binding core consists of the sequence PLLMQALPM, findings that could be corroborated by molecular simulation. The alternative
CLIP peptide was also found to be present in HLA-DQ2 molecules isolated from human thymus. Moreover, the alternative
CLIP peptide was also found in association with
HLA-DQ8. Together, these results indicate that HLA-DQ2 and
HLA-DQ8 associate with an alternative
CLIP sequence, a property that may relate to the strong association between
HLA-DQ molecules and human
autoimmune diseases.