Dominance of an alternative CLIP sequence in the celiac disease associated HLA-DQ2 molecule.
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.
Wiesner
Martina
M
Department of Immunohematology and Blood Transfusion, Leiden University Medical Centre, Leiden, The Netherlands.
Stepniak
Dariusz
D
de Ru
Arnoud H
AH
Moustakis
Antonis K
AK
Drijfhout
Jan W
JW
Papadopoulos
George K
GK
van Veelen
Peter A
PA
Koning
Frits
F
D000595:Amino Acid Sequence; D000944:Antigens, Differentiation, B-Lymphocyte / Q000276:immunology / Q000378:metabolism; D002446:Celiac Disease / Q000276:immunology*; D006683:HLA-DQ Antigens / Q000737:chemistry / Q000235:genetics / Q000276:immunology*; D000949:Histocompatibility Antigens Class II / Q000276:immunology / Q000378:metabolism; D006801:Humans; D013058:Mass Spectrometry; D008958:Models, Molecular; D008969:Molecular Sequence Data; D010455:Peptides / Q000276:immunology / Q000378:metabolism; D011485:Protein Binding; D011487:Protein Conformation
D000944:Antigens, Differentiation, B-Lymphocyte; D006683:HLA-DQ Antigens; C053186:HLA-DQ2 antigen; D000949:Histocompatibility Antigens Class II; D010455:Peptides; C045084:invariant chain