1N19

Structure of the HSOD A4V mutant

1N19 の概要

• エントリーDOI: 10.2210/pdb1n19/pdb
• 関連するPDBエントリー: 1N18
• 分子名称: Superoxide Dismutase [Cu-Zn], COPPER (I) ION, ZINC ION, ... (5 entities in total)
• 機能のキーワード: greek key beta-barrel, oxidoreductase
• 由来する生物種: Homo sapiens (human)
• 細胞内の位置: Cytoplasm: P00441
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 32231.33

構造登録者

Cardoso, R.M.F.,Thayer, M.M.,DiDonato, M.,Lo, T.P.,Bruns, C.K.,Getzoff, E.D.,Tainer, J.A. (登録日: 2002-10-16, 公開日: 2002-11-27, 最終更新日: 2021-10-27)

主引用文献

Cardoso, R.M.F.,Thayer, M.M.,DiDonato, M.,Lo, T.P.,Bruns, C.K.,Getzoff, E.D.,Tainer, J.A.
Insights into Lou Gehrig's disease from the structure and instability of the A4V mutant of human Cu,Zn superoxide dismutase.
J.Mol.Biol., 324:247-256, 2002

PubMed Abstract: Mutations in human superoxide dismutase (HSOD) have been linked to the familial form of amyotrophic lateral sclerosis (FALS). Amyotrophic lateral sclerosis (ALS or Lou Gehrig's disease) is one of the most common neurodegenerative disorders in humans. In ALS patients, selective killing of motor neurons leads to progressive paralysis and death within one to five years of onset. The most frequent FALS mutation in HSOD, Ala4-->Val, is associated with the most rapid disease progression. Here we identify and characterize key differences in the stability between the A4V mutant protein and its thermostable parent (HSOD-AS), in which free cysteine residues were mutated to eliminate interferences from cysteine oxidation. Denaturation studies reveal that A4V unfolds at a guanidine-HCl concentration 1M lower than HSOD-AS, revealing that A4V is significantly less stable than HSOD-AS. Determination and analysis of the crystallographic structures of A4V and HSOD-AS reveal structural features likely responsible for the loss of architectural stability of A4V observed in the denaturation experiments. The combined structural and biophysical results presented here argue that architectural destabilization of the HSOD protein may underlie the toxic function of the many HSOD FALS mutations.

PubMed: 12441104
DOI: 10.1016/S0022-2836(02)01090-2

実験手法

X-RAY DIFFRACTION (1.86 Å)