Abstract
SummaryNumerous 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 ΔN6, a truncation variant of the naturally amyloidogenic protein β2-microglobulin (β2m), to determine the solution structure of a nonnative amyloidogenic intermediate at high resolution. The structure of ΔN6 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 ΔN6 are competent to convert nonamyloidogenic human wild-type β2m (Hβ2m) into a rare amyloidogenic conformation and provide structural evidence for the mechanism by which this conformational conversion occurs.
Highlights
A number of human diseases involve protein misfolding events that result in the malfunctioning of the cellular machinery (Welch, 2004; Gidalevitz et al, 2006)
We show that DN6 is able to interact with human wild-type b2m (Hb2m), causing it to adopt an amyloidcompetent structure and thereby reveal the mechanism of conformational conversion of a naturally occurring amyloidogenic protein in atomistic detail
The results indicate, that DN6 is able to convert Hb2m into a conformer capable of forming amyloid fibrils even when added in catalytic amounts
Summary
A number of human diseases involve protein misfolding events that result in the malfunctioning of the cellular machinery (Welch, 2004; Gidalevitz et al, 2006). In one class of these disorders, normally soluble proteins self-associate to form fibrillar aggregates known as amyloid (Westermark et al, 2007). Studies have suggested that equilibration between a natively folded protein and one or more partially or more highly unfolded species is a key initiating event in amyloid formation (Booth et al, 1997; Calamai et al, 2005). Studies on Alzheimer’s disease, Parkinson’s disease, and systemic and senile amyloidosis (Kane et al, 2000; Lundmark et al, 2002; Rocken and Shakespeare, 2002; Xing et al, 2002; Angot and Brundin, 2009) have suggested that prion-like behavior may be a general feature of misfolded proteins (Brundin et al, 2010).
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