" STRUCTURAL AND FUNCTIONAL STUDY OF A TRANS-ENCODED CLASS II MHC MOLECULE IMPLICATED IN TYPE I DIABETES, AND ENZYMATIC CATALYSIS OF ANTI-BALDWIN RING-CLOSURE IN POLYETHER BIOSYNTHESIS

Abstract

Project 1: Structural and functional study of a trans-encoded class II MHC molecule implicated in type I diabetes Type 1 diabetes is a chronic autoimmune disorder affecting approximately 1 in 300 children and even a greater number of adults. It is an inheritable disorder with strong association with the class II MHC genes HLA-DQ2 and HLA-DQ8. It has been observed that people who carry both these genes have a much higher risk of developing type I diabetes than people who are homozygous for either HLA-DQ8 or HLA-DQ2. One hypothesis is that heterozygous individuals express trans-encoded HLA-DQ molecules which present antigens more efficiently than the cis-encoded counterpart. Our X-ray crystal structure of HLA-DQ8/2 at 3.0 Å resolution shows an unusual MHC:peptide interaction that may, in part, explain the observed phenotype.

Project 2: Enzymatic catalysis of anti-Baldwin ring-closure in polyether biosynthesis There is a 30 year old puzzle in the field of polyether biosynthesis : the cascade of ether ring formation proceeds via the endo pathway instead of the energetically favoured pro-Baldwin, exo pathway. Lsd19 is an epoxide hydrolase from Streptomyces lasaliensis, which catalyzes the formation of two cyclic ether structures found in the polyether natural product Lasalocid A. Interstingly, the first ether ring is formed via the exo pathway while the second ring is formed via the endo pathway. We have determined the X-ray crystal structure of Lsd19 at 1.5 Å resolution. Our structure has revealed both the exo-ring formation and the endo-ring formation catalytic mechanisms.