Genetic and Structural Studies Highlight Novel Key Factors in Autoimmune Diseases

A research team led by scientists from Oxford University (including the Structural Genomics Consortium, the Botnar Research Centre, the Weatherall Institute of Molecular Medicine, the Wellcome Building for Molecular Physiology, and the australian Diamantina Institute in Brisbane), have successfully deciphered the molecular mechanism how an ER protease (ERAP1) functions in a key step in cellular immunity- the processing of peptide antigens that are presented to Major Histocompatibilty Complex 1 (MHC1) molecules.

The team succeeded in determining several crystal structures that provide molecular snapshots along the complex catalytic path. Genome-wide association (GWAS) studies implicate an involvement of ERAP1 in the pathogenesis of chronic inflammatory diseases such as Ankylosing spondylitis (AS) and Psoriasis.

The Oxford group investigated a single nucleotide polymorphism in ERAP1 derived from an AS study and could demonstrate a significantly altered antigen processing pattern, thus highlighting altered antigen presentation as a crucial factor in autoimmunity.

Read more: Kochan G, Krojer T, Harvey D, Fischer R, Chen L, Vollmar M, von Delft F, Kavanagh KL, Brown MA, Bowness P, Wordsworth P, Kessler BM, Oppermann U. Crystal structures of the endoplasmic reticulum aminopeptidase-1 (ERAP1) reveal the molecular basis for N-terminal peptide trimming. PNAS published ahead of print April 20, 2011, doi:10.1073/pnas.1101262108

• Read the article in PNAS (Proceedings of the National Academy of Sciences, USA).
• Read more about the structures: 2YD0, 3QNF