HLA-B27 Subtypes Differentially Associated with Disease Exhibit Subtle Structural Alterations

Martin Hülsmeyer, Roman C. Hillig, Armin Volz, Melanie Rühl, Werner Schröder, Wolfram Saenger, Andreas Ziegler, Barbara Uchanska-Ziegler
2002 Journal of Biological Chemistry  
The reasons for the association of the human major histocompatibility complex protein HLA-B27 with spondyloarthropathies are unknown. To uncover the underlying molecular causes, we determined the crystal structures of the disease-associated B*2705 and the nonassociated B*2709 subtypes complexed with the same nonapeptide (GRFAAAIAK). Both differ in only one residue (Asp 116 and His 116 , respectively) in the Fpocket that accommodates the peptide C terminus. Several different effects of the Asp
more » ... ffects of the Asp 116 3 His replacement are observed. The bulkier His 116 induces a movement of peptide C-terminal pLys 9 , allowing the formation of a novel salt bridge to Asp 77 , whereas the salt bridge between pLys 9 and Asp 116 is converted into a hydrogen bond with His 116 . His 116 but not Asp 116 adopts two alternative conformations, one of which leads to breakage of hydrogen bonds. Water molecules near residue 116 differ with regard to number, position, and contacts made. Furthermore, F-pocket atoms exhibit higher B-factors in B*2709 than in B*2705, indicating an increased flexibility of the entire region in the former subtype. These changes induce subtle peptide conformational alterations that may be responsible for the immunobiological differences between these HLA-B27 subtypes.
doi:10.1074/jbc.m206392200 pmid:12244049 fatcat:hw34hi7fd5dznewz3dyicuhubm