A Phosphomimetic Mutation Stabilizes SOD1 and Rescues Cell Viability in the Context of an ALS-Associated Mutation

James M. Fay, Cheng Zhu, Elizabeth A. Proctor, Yazhong Tao, Wenjun Cui, Hengming Ke, Nikolay V. Dokholyan

Research output: Contribution to journalArticle

11 Citations (Scopus)

Abstract

The majority of amyotrophic lateral sclerosis (ALS)-related mutations in the enzyme Cu,Zn superoxide dismutase (SOD1), as well as a post-translational modification, glutathionylation, destabilize the protein and lead to a misfolded oligomer that is toxic to motor neurons. The biophysical role of another physiological SOD1 modification, T2-phosphorylation, has remained a mystery. Here, we find that a phosphomimetic mutation, T2D, thermodynamically stabilizes SOD1 even in the context of a strongly SOD1-destabilizing mutation, A4V, one of the most prevalent and aggressive ALS-associated mutations in North America. This stabilization protects against formation of toxic SOD oligomers and positively impacts motor neuron survival in cellular assays. We solve the crystal structure of T2D-SOD1 and explain its stabilization effect using discrete molecular dynamics (DMD) simulations. These findings imply that T2-phosphorylation may be a plausible innate cellular protection response against SOD1-induced cytotoxicity, and stabilizing the SOD1 native conformation might offer us viable pharmaceutical strategies against currently incurable ALS.

Original languageEnglish (US)
Pages (from-to)1898-1906
Number of pages9
JournalStructure
Volume24
Issue number11
DOIs
StatePublished - Nov 1 2016

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Amyotrophic Lateral Sclerosis
Cell Survival
Mutation
Poisons
Motor Neurons
Phosphorylation
Molecular Dynamics Simulation
Post Translational Protein Processing
North America
Enzymes
Pharmaceutical Preparations
Proteins

All Science Journal Classification (ASJC) codes

  • Structural Biology
  • Molecular Biology

Cite this

Fay, James M. ; Zhu, Cheng ; Proctor, Elizabeth A. ; Tao, Yazhong ; Cui, Wenjun ; Ke, Hengming ; Dokholyan, Nikolay V. / A Phosphomimetic Mutation Stabilizes SOD1 and Rescues Cell Viability in the Context of an ALS-Associated Mutation. In: Structure. 2016 ; Vol. 24, No. 11. pp. 1898-1906.
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A Phosphomimetic Mutation Stabilizes SOD1 and Rescues Cell Viability in the Context of an ALS-Associated Mutation. / Fay, James M.; Zhu, Cheng; Proctor, Elizabeth A.; Tao, Yazhong; Cui, Wenjun; Ke, Hengming; Dokholyan, Nikolay V.

In: Structure, Vol. 24, No. 11, 01.11.2016, p. 1898-1906.

Research output: Contribution to journalArticle

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