5K02

Structure of human SOD1 with T2D mutation

5K02 の概要

• エントリーDOI: 10.2210/pdb5k02/pdb
• 分子名称: Superoxide dismutase [Cu-Zn], COPPER (II) ION, ZINC ION, ... (4 entities in total)
• 機能のキーワード: sod1, phosphomimetic mutation, oxidoreductase
• 由来する生物種: Homo sapiens (Human)
• タンパク質・核酸の鎖数: 24
• 化学式量合計: 383292.00

構造登録者

Fay, J.M.,Zhu, C.,Cui, W.,Ke, H.,Dokholyan, N.V. (登録日: 2016-05-17, 公開日: 2016-11-23, 最終更新日: 2024-10-23)

主引用文献

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

実験手法

X-RAY DIFFRACTION (1.99 Å)