Misfolding and aggregation of Cu, Zn Superoxide dismutase (SOD1) is involved in the neurodegenerative disease, amyotrophic lateral sclerosis. 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 when compared with wild-type and mutant monomeric SOD1. At higher concentrations of TFE, a native-like structure with the increase in α-helical content was observed. The molecular dynamics simulation results illustrate distinct structural dynamics for different regions of SOD1 variants and show 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.
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Cover Image
A high-resolution crystal structure of the molybdenum insertase Cnx1E from Arabidopsis thaliana reveals two mutually exclusive molybdate binding sites, that have mechanistic implications for the Mo-insertion process into the pterin moiety of the molybdenum cofactor. In this issue of the Biochemical Journal, Kruse et al. found that molybdate is sequentially bound to the entry and the catalytically-productive site, going hand in hand with a distinct backbone conformation shift. In this image, adenylated molybdopterin and the two molybdate ions are shown in front of the Cnx1E active site. (Image provided by J. Krausze, W. A. Sassen and T. Kruse); for details see pages 1739–1753.
TFE-induced local unfolding and fibrillation of SOD1: bridging the experiment and simulation studies
Vijay Kumar, Amresh Prakash, Preeti Pandey, Andrew M. Lynn, Md. Imtaiyaz Hassan; TFE-induced local unfolding and fibrillation of SOD1: bridging the experiment and simulation studies. Biochem J 31 May 2018; 475 (10): 1701–1719. doi: https://doi.org/10.1042/BCJ20180085
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