TY - JOUR
T1 - Folding of Cu, Zn superoxide dismutase and familial amyotrophic lateral sclerosis
AU - Khare, Sagar D.
AU - Ding, Feng
AU - Dokholyan, Nikolay V.
N1 - Funding Information:
We thank S. V. Buldyrev for his help with DMD simulations, B. N. Dominy for help with CHARMM calculations and J. M. Borreguero, L. J. Hayward, B. Kuhlman and Z. Xu for helpful discussions. We acknowledge the support of the UNC-CH Research Council Grant. S.D.K. acknowledges the support of Scholars for Tomorrow Fellowship of UNC Graduate School.
PY - 2003/11/28
Y1 - 2003/11/28
N2 - 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.
AB - 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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U2 - 10.1016/j.jmb.2003.09.069
DO - 10.1016/j.jmb.2003.09.069
M3 - Article
C2 - 14623191
AN - SCOPUS:0242662235
SN - 0022-2836
VL - 334
SP - 515
EP - 525
JO - Journal of Molecular Biology
JF - Journal of Molecular Biology
IS - 3
ER -