Molecular dynamics of a far positioned SOD1 mutant V14M reveals pathogenic misfolding behavior

Abstract

Human superoxide dismutase (Cu/Zn SOD1) is a homodimeric enzyme. Mutations in Cu/Zn SOD1 causes a familial form of amyotrophic lateral sclerosis (fALS), and aggregation of mutant SOD1 has been proposed to play a role in neurodegeneration. Though a majority of the mutations are point substitutions, there are a few changes that result in amino acid deletions or truncations of the polypeptide. These pathogenic mutations are scattered throughout the three-dimensional structure of the dimeric enzyme, which creates a puzzling pattern to investigate the molecular determinants of fALS. The most common hypothesis proposed that the misfolding of SOD1 mutants are primarily triggered by decreased affinity for metal ions. However, this hypothesis is challenging, as a significant number of disease-causing mutations are located far away from the metal-binding site and dimer interface. So in the present study, we have investigated the influence of such a far positioned pathogenic mutation, V14M, in altering the stability and folding of the Cu/Zn SOD1. Though the location of Val14 is far positioned, it has a vital role in the stability of SOD1 by preserving its hydrophobic cluster at one end of the β barrel domain. We have performed MD simulations of the V14M mutant for 80 ns timescale. The results reveal the fact that irrespective of its location, V14M mutation triggers a conformational change that is more similar to that of the metal-deficient holo form and could resemble an intermediate state in the folding reaction which results in protein misfolding and aggregation.

Keywords:

• protein structure
• mutation
• misfolding
• protein conformational disorders
• SOD1

Acknowledgments

The authors thank the reviewers for their constructive comments. DT acknowledges the graduate students V. Sai Niveditha and S. Renukhadevi for the helpful discussions. KS gratefully acknowledges DST-SERB (DST No: SB/FT/LS-385/2012) for financial support through Fast Track scheme for Young Scientists and DST-FIST (SR/FST/LSI-587/2014), Government of India. The authors gratefully acknowledge the management of SASTRA University for the encouragement and the financial support to DT.