Understanding and targeting protein-protein interactions in early amyloid assembly (360G-Wellcome-105222_Z_14_Z)

A major aim of the project includes investigating the early protein-protein interactions involved in the formation of amyloid fibrils from a beta2m variant with a D76N amino acid change, which has been identified as the causative agent in a hereditary, systemic and fatal amyloidosis disease. The D76N associated disease has a different pathology to that of wild-type beta2m associated dialysis related amyloidosis therefore a key goal is to understand how the amino acid change D76N affects the structure and dynamics of the protein and how this results in altered pathology. Another key aim is to refine the structure of the kinetically trapped, inhibitory complex formed between murine beta 2m (mbeta2m) and the truncated form of human beta2m DeltaN6, known to promote beta2m aggregation. A combination of small molecule and peptide screening will be employed to identify an inhibitor of DeltaN6 aggregation, guided by structural information about the DeltaN6-mbeta2m interface.