Conformational Conversion during Amyloid Formation at Atomic Resolution

Numerous studies of amyloid assembly have indicated that partially folded protein species are responsible for initiating aggregation. Despite their importance, the structural and dynamic features of amyloidogenic intermediates and the molecular details of how they cause aggregation remain elusive. Here, we use Delta N6, a truncation variant of the naturally amyloidogenic protein beta(2)-microglobulin (beta(2)m), to determine the solution structure of a nonnative amyloidogenic intermediate at high resolution. The structure of Delta N6 reveals a major repacking of the hydrophobic core to accommodate the nonnative peptidyl-prolyl trans-isomer at Pro32. These structural changes, together with a concomitant pH-dependent enhancement in backbone dynamics on a microsecond-millisecond timescale, give rise to a rare conformer with increased amyloidogenic potential. We further reveal that catalytic amounts of Delta N6 are competent to convert nonamyloidogenic human wild-type beta(2)m (H beta(2)m) into a rare amyloidogenic conformation and provide structural evidence for the mechanism by which this conformational conversion occurs.