Direct Observation of β-Barrel Intermediates in the Self-Assembly of Toxic SOD128–38 and Absence in Nontoxic Glycine Mutants
aggregation intermediates
β- barrels
0301 basic medicine
Amyloid
Chemical Sciences not elsewhere classified
Biophysics
Glycine
Biochemistry
G 33V mutants
mutants G 33V
03 medical and health sciences
superoxide dismutase 1
Superoxide Dismutase-1
single-layer β- sheets
SOD
β- sheet-rich oligomers
Cancer
Nontoxic Glycine Mutants Soluble lo.
0303 health sciences
Amyloid beta-Peptides
Ecology
Superoxide Dismutase
amyloid
33W
β- barrel oligomers
two-layer β- sheets
Protein Conformation, beta-Strand
Neuroscience
Single-point glycine substitutions
DOI:
10.1021/acs.jcim.0c01319
Publication Date:
2021-01-15T05:02:58Z
AUTHORS (4)
ABSTRACT
Soluble low-molecular-weight oligomers formed during the early stage of amyloid aggregation are considered the major toxic species in amyloidosis. The structure-function relationship between oligomeric assemblies and the cytotoxicity in amyloid diseases are still elusive due to the heterogeneous and transient nature of these aggregation intermediates. To uncover the structural characteristics of toxic oligomeric intermediates, we compared the self-assembly dynamics and structures of SOD128-38, a cytotoxic fragment of the superoxide dismutase 1 (SOD1) associated with the amyotrophic lateral sclerosis, with its two nontoxic mutants G33V and G33W using molecular dynamics simulations. Single-point glycine substitutions in SOD128-38 have been reported to abolish the amyloid toxicity. Our simulation results showed that the toxic SOD128-38 and its nontoxic mutants followed different aggregation pathways featuring distinct aggregation intermediates. Specifically, wild-type SOD128-38 initially self-assembled into random-coil-rich oligomers, among which fibrillar aggregates composed of well-defined curved single-layer β-sheets were nucleated via coil-to-sheet conversions and the formation of β-barrels as intermediates. In contrast, the nontoxic G33V/G33W mutants readily assembled into small β-sheet-rich oligomers and then coagulated with each other into cross-β fibrils formed by two-layer β-sheets without forming β-barrels as the intermediates. The direct observation of β-barrel oligomers during the assembly of toxic SOD128-38 fragments but not the nontoxic glycine-substitution mutants strongly supports β-barrels as the toxic oligomers in amyloidosis, probably via interactions with the cell membrane and forming amyloid pores. With well-defined structures, the β-barrel might serve as a novel therapeutic target against amyloid-related diseases.
SUPPLEMENTAL MATERIAL
Coming soon ....
REFERENCES (58)
CITATIONS (19)
EXTERNAL LINKS
PlumX Metrics
RECOMMENDATIONS
FAIR ASSESSMENT
Coming soon ....
JUPYTER LAB
Coming soon ....