Direct Observation of β-Barrel Intermediates in the Self-Assembly of Toxic SOD128–38 and Absence in Nontoxic Glycine Mutants

• DOI: 10.1021/acs.jcim.0c01319
• Publication Date: 2021-01-15T05:02:58Z
• Authors: Yunxiang Sun; Junchao Huang; Xiangmei Duan; Feng Ding
• Keywords: Amyloid (mycology); Random coil

Soluble low-molecular-weight oligomers formed during the early stage of amyloid aggregation are considered major toxic species in amyloidosis. The structure-function relationship between oligomeric assemblies and cytotoxicity diseases still elusive due to heterogeneous transient nature these intermediates. To uncover structural characteristics intermediates, we compared self-assembly dynamics structures SOD128-38, a cytotoxic fragment superoxide dismutase 1 (SOD1) associated with amyotrophic lateral sclerosis, its two nontoxic mutants G33V G33W using molecular simulations. Single-point glycine substitutions SOD128-38 have been reported abolish toxicity. Our simulation results showed that followed different pathways featuring distinct Specifically, wild-type initially self-assembled into random-coil-rich oligomers, among which fibrillar aggregates composed well-defined curved single-layer β-sheets were nucleated via coil-to-sheet conversions formation β-barrels as In contrast, G33V/G33W readily assembled small β-sheet-rich then coagulated each other cross-β fibrils by two-layer without forming direct observation β-barrel assembly fragments but not glycine-substitution strongly supports amyloidosis, probably interactions cell membrane pores. With structures, might serve novel therapeutic target against amyloid-related diseases.