Structural studies of thyroid peroxidase show the monomer interacting with autoantibodies in thyroid autoimmune disease [article]

Daniel E Williams, Sarah N Le, David E Hoke, Peter G Chandler, Monika Gora, Marlena Godlewska, J Paul Banga, Ashley M Buckle
2019 bioRxiv   pre-print
Thyroid peroxidase (TPO) is a critical membrane-bound enzyme involved in the biosynthesis of multiple thyroid hormones, and is a major autoantigen in autoimmune thyroid diseases such as Graves' disease and Hashimoto's thyroiditis. Here we report the biophysical and structural characterisation of two novel TPO constructs containing only the ectodomain of TPO and lacking the propeptide. Both constructs were enzymatically active and able to bind the patient-derived TR1.9 autoantibody. Analytical
more » ... ibody. Analytical ultra-centrifugation data suggests that TPO can exist as both a monomer and a dimer. Combined with negative stain electron microscopy and molecular dynamics simulations, these data show that TR1.9 autoantibody preferentially binds the TPO monomer, revealing conformational changes that bring together previously disparate residues into a continuous epitope. In addition to providing plausible structural models of a TPO-autoantibody complex, this study provides validated TPO constructs that will facilitate further characterization, and advances our understanding of the structural, functional and antigenic characteristics of TPO, a molecule behind some of the most common autoimmune diseases.
doi:10.1101/2019.12.15.876789 fatcat:ghanffkzz5av5embcsnxyma7aa