Folding of Cu, Zn superoxide dismutase and Familial Amyotrophic Lateral Sclerosis

Sagar D. Khare; Feng Ding; Nikolay V. Dokholyan

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Folding of Cu, Zn superoxide dismutase and Familial Amyotrophic Lateral Sclerosis

Sagar D. Khare·Feng Ding·Nikolay V. Dokholyan

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Abstract

Cu,Zn superoxide dismutase (SOD1) has been implicated in the familial form of the neurodegenerative disease Amyotrophic Lateral Sclerosis (ALS). It has been suggested that mutant mediated SOD1 misfolding/aggregation is an integral part of the pathology of ALS. We study the folding thermodynamics and kinetics of SOD1 using a hybrid molecular dynamics approach. We reproduce the experimentally observed SOD1 folding thermodynamics and find that the residues which contribute the most to SOD1 thermal stability are also crucial for apparent two-state folding kinetics. Surprisingly, we find that these residues are located on the surface of the protein and not in the hydrophobic core. Mutations in some of the identified residues are found in patients with the disease. We argue that the identified residues may play an important role in aggregation. To further characterize the folding of SOD1, we study the role of cysteine residues in folding and find that non-native disulfide bond formation may significantly alter SOD1 folding dynamics and aggregation propensity.

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Sagar D. Khare, Feng Ding, Nikolay V. Dokholyan. 2003-06-30. Folding of Cu, Zn superoxide dismutase and Familial Amyotrophic Lateral Sclerosis. https://arxiv.org/abs/physics/0306200

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