Title
TFE-induced local unfolding and fibrillation of SOD1: bridging the experiment and simulation studies
Author
Vijay Kumar, Amresh Prakash, Preeti Pandey, Andrew M Lynn, Imtaiyaz Hassan
Year
2018
Journal
Biochemical Journal
Abstract
Misfolding and aggregation of Cu, Zn Superoxide dismutase (SOD1) is involved in the neurodegenerative disease, amyotrophic lateral sclerosis (ALS). Many studies have shown that metal depleted, monomeric form of SOD1 displays substantial local unfolding dynamics and is the precursor for aggregation. Here we have studied the structure and dynamics of different apo monomeric SOD1 variants associated with unfolding and aggregation in aqueous trifluoroethanol (TFE) through experiments and simulation. TFE induces partially unfolded β-sheet-rich extended conformations in these SOD1 variants, which subsequently develops aggregates with fibril like characteristics. Fibrillation was achieved more easily in disulfide-reduced monomeric SOD1 as compared to wild-type and mutant monomeric SOD1. At higher concentrations of TFE, a native-like structure with increase in α-helical content was observed. The molecular dynamics (MD) simulation results illustrate distinct structural dynamics for different regions of SOD1 variants and shows uniform local unfolding of β-strands. The strands protected by the zinc-binding and electrostatic loops were found to unfold first in 20% (v/v) TFE, leading to a partial unfolding of β-strands 4, 5 and 6 which are prone to aggregation. Our results thus shed light on the role of local unfolding and conformational dynamics in SOD1 misfolding and aggregation.
Instrument
J-810
Keywords
Circular dichroism, Secondary structure, Chemical stability, Aggregation, Protein folding, Biochemistry