5K02

Structure of human SOD1 with T2D mutation

Summary for 5K02

• Entry DOI: 10.2210/pdb5k02/pdb
• Descriptor: Superoxide dismutase [Cu-Zn], COPPER (II) ION, ZINC ION, ... (4 entities in total)
• Functional Keywords: sod1, phosphomimetic mutation, oxidoreductase
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 24
• Total formula weight: 383292.00

Authors

Fay, J.M.,Zhu, C.,Cui, W.,Ke, H.,Dokholyan, N.V. (deposition date: 2016-05-17, release date: 2016-11-23, Last modification date: 2024-10-23)

Primary citation

Fay, J.M.,Zhu, C.,Proctor, E.A.,Tao, Y.,Cui, W.,Ke, H.,Dokholyan, N.V.
A Phosphomimetic Mutation Stabilizes SOD1 and Rescues Cell Viability in the Context of an ALS-Associated Mutation.
Structure, 24:1898-1906, 2016

PubMed 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.

PubMed: 27667694
DOI: 10.1016/j.str.2016.08.011

Experimental method

X-RAY DIFFRACTION (1.99 Å)