6FLH

Monomeric Human Cu,Zn Superoxide dismutase, SOD1 7+7, apo form

6FLH の概要

• エントリーDOI: 10.2210/pdb6flh/pdb
• 分子名称: Superoxide dismutase [Cu-Zn], SULFATE ION, GLYCEROL, ... (4 entities in total)
• 機能のキーワード: sod1, oxidoreductase
• 由来する生物種: Homo sapiens (Human)
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 12075.28

構造登録者

Wang, H.,Yang, F.,Logan, D.,Oliveberg, M. (登録日: 2018-01-25, 公開日: 2018-11-07, 最終更新日: 2024-01-17)

主引用文献

Yang, F.,Wang, H.,Logan, D.T.,Mu, X.,Danielsson, J.,Oliveberg, M.
The Cost of Long Catalytic Loops in Folding and Stability of the ALS-Associated Protein SOD1.
J.Am.Chem.Soc., 140:16570-16579, 2018

PubMed Abstract: A conspicuous feature of the amyotrophic lateral sclerosis (ALS)-associated protein SOD1 is that its maturation into a functional enzyme relies on local folding of two disordered loops into a catalytic subdomain. To drive the disorder-to-order transition, the protein employs a single Zn ion. The question is then if the entropic penalty of maintaining such disordered loops in the immature apoSOD1 monomer is large enough to explain its unusually low stability, slow folding, and pathological aggregation in ALS. To find out, we determined the effects of systematically altering the SOD1-loop lengths by protein redesign. The results show that the loops destabilize the apoSOD1 monomer by ∼3 kcal/mol, rendering the protein marginally stable and accounting for its aggregation behavior. Yet the effect on the global folding kinetics remains much smaller with a transition-state destabilization of <1 kcal/mol. Notably, this 1/3 transition-state to folded-state stability ratio provides a clear-cut example of the enigmatic disagreement between the Leffler α value from loop-length alterations (typically 1/3) and the "standard" reaction coordinates based on solvent perturbations (typically >2/3). Reconciling the issue, we demonstrate that the disagreement disappears when accounting for the progressive loop shortening that occurs along the folding pathway. The approach assumes a consistent Flory loop entropy scaling factor of c = 1.48 for both equilibrium and kinetic data and has the added benefit of verifying the tertiary interactions of the folding nucleus as determined by phi-value analysis. Thus, SOD1 not only represents a case where evolution of key catalytic function has come with the drawback of a destabilized apo state but also stands out as a well-suited model system for exploring the physicochemical details of protein self-organization.

PubMed: 30359015
DOI: 10.1021/jacs.8b08141

実験手法

X-RAY DIFFRACTION (1.79 Å)