title: Polyanion binding accelerates the formation of stable and low-toxic aggregates of ALS-linked SOD1 mutant A4V.
abstract: The toxic property thus far shared by both ALS-linked SOD1 variants and wild-type SOD1 is an increased propensity to aggregation. However, whether SOD1 oligomers or aggregates are toxic to cells remains to be well defined. Moreover, how the toxic SOD1 species are removed from intra- and extracellular environments also needs to be further explored. The DNA binding has been shown to be capable of accelerating the aggregatio\n of wild-type and oxidized SOD1 forms under acidic and neutral conditions. In this study, we explore the binding of DNA and heparin, two types of essential life polyanions, to A4V, an ALS-linked SOD1 mutant, under acidic conditions, and its consequences. The polyanion binding alters the A4V conformation, neutralizes its local positive charges, and increases its local concentrations along the polyanion chain, which are sufficient to lead to acceleration of the pH-dependent A4V aggregation. The accelerated aggregation, which is ascribed to the polyanion binding-mediated removal or shortening of the lag phase in aggregation, contributes to the formation of amorphous A4V nanoparticles. The prolonged incubation with polyanions not only results in the complete conversion of likely soluble toxic A4V oligomers into non- and low-toxic SDS-resistant aggregates, but also increases their stability. Although this is only an initial step toward reducing the toxicity of SOD1 mutants, the accelerating role of polyanions in protein aggregation might become one of the rapid pathways that remove toxic forms of SOD1 mutants from intra- and extracellular environments.
authors.affiliation: Key Laboratory of Pesticide & Chemical Biology, Ministry of Education and School of Chemistry, Central China Normal University, Wuhan, 430079, China.
authors.forename: Dan
authors.initials: D
authors.lastname: Zhao
authors.forename: Shibing
authors.initials: S
authors.lastname: Zhang
authors.forename: Yan
authors.initials: Y
authors.lastname: Meng
authors.forename: Dong
authors.initials: D
authors.lastname: Xiongwei
authors.forename: Dan
authors.initials: D
authors.lastname: Zhang
authors.forename: Yi
authors.initials: Y
authors.lastname: Liang
authors.forename: Li
authors.initials: L
authors.lastname: Wang
authors.forename: Changlin
authors.initials: C
authors.lastname: Liu
mesh_terms: D019943:Amino Acid Substitution; D000690:Amyotrophic Lateral Sclerosis / Q000201:enzymology / Q000235:genetics*; D001667:Binding, Competitive; D002460:Cell Line; D002470:Cell Survival; D004247:DNA / Q000737:chemistry* / Q000378:metabolism; D006495:Heparin, Low-Molecular-Weight / Q000737:chemistry* / Q000378:metabolism; D006801:Humans; D006863:Hydrogen-Ion Concentration; D057927:Hydrophobic and Hydrophilic Interactions; D008958:Models, Molecular; D009154:Mutation; D009474:Neurons / Q000378:metabolism; D066263:Protein Aggregation, Pathological; D011487:Protein Conformation; D055550:Protein Stability; D011994:Recombinant Proteins / Q000737:chemistry / Q000378:metabolism; D013482:Superoxide Dismutase / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D000072105:Superoxide Dismutase-1; D013499:Surface Properties; D015854:Up-Regulation
chemical_list: D006495:Heparin, Low-Molecular-Weight; D011994:Recombinant Proteins; C000606290:SOD1 protein, human; D004247:DNA; D013482:Superoxide Dismutase; D000072105:Superoxide Dismutase-1
keywords: A4V; Cu/Zn superoxide dismutase (SOD1); DNA; acceleration; aggregation; heparin