The Structure of a Peptide-Loaded Shark MHC Class I Molecule Reveals Features of the Binding between β2-Microglobulin and H Chain Conserved in Evolution

Cartilaginous fish are the most primitive extant species with MHC molecules. Using the nurse shark, the current study is, to the best of our knowledge, the first to present a peptide-loaded MHC class I (pMHC-I) structure for this class of animals. The overall structure was found to be similar between cartilaginous fish and bony animals, showing remarkable conservation of interactions between the three pMHC-I components H chain, beta(2)-microglobulin (beta(2)-m), and peptide ligand. In most previous studies, relatively little attention was given to the details of binding between the H chain and beta(2)-m, and our study provides important new insights. A pronounced conserved feature involves the insertion of a large beta(2)-m F56+W60 hydrophobic knob into a pleat of the beta-sheet floor of the H chain alpha 1 alpha 2 domain, with the knob being surrounded by conserved residues. Another conserved feature is a hydrogen bond between beta(2)-m Y10 and a proline in the alpha 3 domain of the H chain. By alanine substitution analysis, we found that the conserved beta(2)-m residues Y10, D53, F56, and W60-each binding the H chain-are required for stable pMHC-I complex formation. For the beta(2)-m residues Y10 and F56, such observations have not been reported before. The combined data indicate that for stable pMHC-I complex formation beta(2)-m should not only bind the alpha 1 alpha 2 domain but also the alpha 3 domain. Knowing the conserved structural features of pMHC-I should be helpful for future elucidations of the mechanisms of pMHC-I complex formation and peptide editing.

Automated summary

Cartilaginous fish, the most primitive extant species with MHC molecules, share a similar pMHC-I structure with bony animals, highlighting the conservation of interactions. The study emphasizes the importance of specific beta(2)-m residues in stable pMHC-I complex formation, providing new insights into the mechanisms of pMHC-I complex formation and peptide editing.