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.
journal_name
Elifejournal_title
eLifeauthors
Sekhar A,Rumfeldt JA,Broom HR,Doyle CM,Bouvignies G,Meiering EM,Kay LEdoi
10.7554/eLife.07296subject
Has Abstractpub_date
2015-06-23 00:00:00pages
e07296issn
2050-084Xjournal_volume
4pub_type
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