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

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2017-04-09 发布于江苏
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Folding of Cu, Zn superoxide dismutase and Familial Amyotrophic Lateral Sclerosis.pdf

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

a r X i v : p h y s i c s / 0 3 0 6 2 0 0 v 2 [ p h y s i c s .b i o - p h ] 3 0 J u n 2 0 0 3 1 Folding of Cu, Zn superoxide dismutase and Familial Amyotrophic Lateral Sclerosis Sagar D. Khare?, Feng Ding? and Nikolay V. Dokholyan?1 ?Department of Biochemistry and Biophysics, University of North Carolina at Chapel Hill, School of Medicine, Chapel Hill, NC 27599, USA ?Center for Polymer Studies, Department of Physics, Boston University, Boston, MA 02215, USA Summary Cu,Zn superoxide dismutase (SOD1) has been implicated in the familial form of the neurodegen- erative 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 ther- modynamics 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. Surpris- ingly, 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. Keywords: Cu,Zn superoxide dismutase, Familial Amyotrophic Lateral Sclerosis, molecular dynamics simulations, aggregation, misfolding. 1 Corresponding author, Email: dokh@ 2I. INTRODUCTION ALS is the most common motor neuron disease in human adults that is characterized by selective motor neuron death [1, 2, 3, 4]. In approximately 10% of the cases of ALS, the disease is inherited, thus called Familial ALS (FALS) [1]. Mutations in the cytopl