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 Cited by 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: 27667694DOI: 10.1016/j.str.2016.08.011 PDB entries with the same primary citation |
Experimental method | X-RAY DIFFRACTION (1.99 Å) |
Structure validation
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