Promiscuous antigen presentation by the nonclassical MHC Ib Qa-2 is enabled by a shallow, hydrophobic groove and self-stabilized peptide conformation.
BACKGROUND
Qa-2 is a nonclassical MHC Ib antigen, which has been implicated in both innate and adaptive immune responses, as well as embryonic development. Qa-2 has an unusual peptide binding specificity in that it requires two dominant C-terminal anchor residues and is capable of associating with a substantially more diverse array of peptide sequences than other nonclassical MHC.


RESULTS
We have determined the crystal structure, to 2.3 A, of the Q9 gene of murine Qa-2 complexed with a self-peptide derived from the L19 ribosomal protein, which is abundant in the pool of peptides eluted from the Q9 groove. The 9 amino acid peptide is bound high in a shallow, hydrophobic binding groove of Q9, which is missing a C pocket. The peptide makes few specific contacts and exhibits extremely poor shape complementarity to the MHC groove, which facilitates the presentation of a degenerate array of sequences. The L19 peptide is in a centrally bulged conformation that is stabilized by intramolecular interactions from the invariant P7 histidine anchor residue and by a hydrophobic core of preferred secondary anchor residues that have minimal interaction with the MHC.


CONCLUSIONS
Unexpectedly, the preferred secondary peptide residues that exhibit tenuous contact with Q9 contribute significantly to the overall stability of the peptide-MHC complex. The structure of this complex implies a "conformational" selection by Q9 for peptide residues that optimally stabilize the large bulge rather than making intimate contact with the MHC pockets.
He
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Department of Microbiology and Immunology, Stanford University School of Medicine, Stanford, CA 94305, USA.
Tabaczewski
P
P
Ho
J
J
Stroynowski
I
I
Garcia
K C
KC
D000818:Animals; D017951:Antigen Presentation; D018360:Crystallography, X-Ray; D004797:Enzyme-Linked Immunosorbent Assay; D005805:Genes, MHC Class I / Q000276:immunology*; D015395:Histocompatibility Antigens Class I / Q000737:chemistry* / Q000276:immunology*; D006860:Hydrogen Bonding; D051379:Mice; D008810:Mice, Inbred C57BL; D008958:Models, Molecular; D010455:Peptides / Q000737:chemistry*; D011485:Protein Binding; D011487:Protein Conformation; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013154:Spleen / Q000378:metabolism
D015395:Histocompatibility Antigens Class I; C448919:MHC Ib Qa-2 antigen; D010455:Peptides