TY - JOUR
T1 - Structural and thermodynamic effects of post-translational modifications in mutant and wild type Cu, Zn superoxide dismutase
AU - Proctor, Elizabeth Anne
AU - Ding, Feng
AU - Dokholyan, Nikolay
N1 - Funding Information:
The authors thank Dr Michael Caplow, Rachel Redler, Dr Kyle Wilcox, Dr Lanette Fee, Pradeep Kota and Srinivas Ramachandran for helpful discussions. This work was supported by the National Institutes of Health grant number R01GM080742 and ARRA supplements GM080742-03S1 and GM066940-06S1 . E.A.P. was supported by the UNC Curriculum in Bioinformatics and Computational Biology and National Institute of Health Predoctoral Fellowship F31AG039266-01 from the National Institute on Aging.
PY - 2011/5/6
Y1 - 2011/5/6
N2 - Aggregation of Cu,Zn superoxide dismutase (SOD1) is implicated in amyotrophic lateral sclerosis. Glutathionylation and phosphorylation of SOD1 is omnipresent in the human body, even in healthy individuals, and has been shown to increase SOD1 dimer dissociation, which is the first step on the pathway toward SOD1 aggregation. We found that post-translational modification of SOD1, especially glutathionylation, promotes dimer dissociation. We discovered an intermediate state in the pathway to dissociation, a conformational change that involves a "loosening" of the β-barrels and a loss or shift of dimer interface interactions. In modified SOD1, this intermediate state is stabilized as compared to unmodified SOD1. The presence of post-translational modifications could explain the environmental factors involved in the speed of disease progression. Because post-translational modifications such as glutathionylation are often induced by oxidative stress, post-translational modification of SOD1 could be a factor in the occurrence of sporadic cases of amyotrophic lateral sclerosis, which represent 90% of all cases of the disease.
AB - Aggregation of Cu,Zn superoxide dismutase (SOD1) is implicated in amyotrophic lateral sclerosis. Glutathionylation and phosphorylation of SOD1 is omnipresent in the human body, even in healthy individuals, and has been shown to increase SOD1 dimer dissociation, which is the first step on the pathway toward SOD1 aggregation. We found that post-translational modification of SOD1, especially glutathionylation, promotes dimer dissociation. We discovered an intermediate state in the pathway to dissociation, a conformational change that involves a "loosening" of the β-barrels and a loss or shift of dimer interface interactions. In modified SOD1, this intermediate state is stabilized as compared to unmodified SOD1. The presence of post-translational modifications could explain the environmental factors involved in the speed of disease progression. Because post-translational modifications such as glutathionylation are often induced by oxidative stress, post-translational modification of SOD1 could be a factor in the occurrence of sporadic cases of amyotrophic lateral sclerosis, which represent 90% of all cases of the disease.
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U2 - 10.1016/j.jmb.2011.03.004
DO - 10.1016/j.jmb.2011.03.004
M3 - Article
C2 - 21396374
AN - SCOPUS:79953848210
SN - 0022-2836
VL - 408
SP - 555
EP - 567
JO - Journal of Molecular Biology
JF - Journal of Molecular Biology
IS - 3
ER -