Thermal fluctuations of immature SOD1 lead to separate folding and misfolding pathways.
Elife
; 4: e07296, 2015 Jun 23.
Article
in En
| MEDLINE
| ID: mdl-26099300
ABSTRACT
Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease involving cytotoxic conformations of Cu, Zn superoxide dismutase (SOD1). A major challenge in understanding ALS disease pathology has been the identification and atomic-level characterization of these conformers. Here, we use a combination of NMR methods to detect four distinct sparsely populated and transiently formed thermally accessible conformers in equilibrium with the native state of immature SOD1 (apoSOD1(2SH)). Structural models of two of these establish that they possess features present in the mature dimeric protein. In contrast, the other two are non-native oligomers in which the native dimer interface and the electrostatic loop mediate the formation of aberrant intermolecular interactions. Our results show that apoSOD1(2SH) has a rugged free energy landscape that codes for distinct kinetic pathways leading to either maturation or non-native association and provide a starting point for a detailed atomic-level understanding of the mechanisms of SOD1 oligomerization.
Key words
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Superoxide Dismutase
/
Protein Folding
Limits:
Humans
Language:
En
Journal:
Elife
Year:
2015
Document type:
Article
Affiliation country:
Canada