The role of the I_T-state in D76N β₂-microglobulin amyloid assembly: A crucial intermediate or an innocuous bystander?

ABSTRACT: The D76N variant of human β₂-microglobulin (β₂m) is the causative agent of a hereditary amyloid disease. Interestingly, D76N-associated amyloidosis has a distinctive pathology compared with aggregation of WT-β₂m, which occurs in dialysis-related amyloidosis. A folding intermediate of WT-β₂m, known as the I_T-state, which contains a nonnative trans Pro-32, has been shown to be a key precursor of WT-β₂m aggregation in vitro However, how a single amino acid substitution enhances the rate of aggregation of D76N-β₂m and gives rise to a different amyloid disease remained unclear. Using real-time refolding experiments monitored by CD and NMR, we show that the folding mechanisms of WT- and D76N-β₂m

SUBMITTER: Smith HI 

PROVIDER: S-EPMC7458819 | biostudies-literature | 2020 Aug

REPOSITORIES: biostudies-literature