title: Ligand binding and aggregation of pathogenic SOD1.
abstract: Mutations in the gene encoding Cu/Zn superoxide dismutase-1 cause amyotrophic lateral sclerosis. Superoxide dismutase-1 mutations decrease protein stability and promote aggregation. The mutant monomer is thought to be an intermediate in the pathway from the superoxide dismutase-1 dimer to aggregate. Here we find that the monomeric copper-apo, zinc-holo protein is structurally perturbed and the apo-protein aggregates without reattainment of the monomer-dimer equilibrium. Intervention to stabilize the superoxide dismutase-1 dimer and inhibit aggregation is regarded as a potential therapeutic strategy. We describe protein-ligand interactions for two compounds, Isoproterenol and 5-fluorouridine, highlighted as superoxide dismutase-1 stabilizers. We find both compounds interact with superoxide dismutase-1 at a key region identified at the core of the superoxide dismutase-1 fibrillar aggregates, β-barrel loop II-strand 3, rather than the proposed dimer interface site. This illustrates the need for direct structural observations when developing compounds for protein-targeted therapeutics.
authors.affiliation: Molecular Biophysics Group, Institute of Integrative Biology, Faculty of Health and Life Sciences, University of Liverpool, Liverpool L69 7ZB, UK.
authors.forename: Gareth S A
authors.initials: GS
authors.lastname: Wright
authors.forename: Svetlana V
authors.initials: SV
authors.lastname: Antonyuk
authors.forename: Neil M
authors.initials: NM
authors.lastname: Kershaw
authors.forename: Richard W
authors.initials: RW
authors.lastname: Strange
authors.forename: S
authors.initials: S
authors.lastname: Samar Hasnain
mesh_terms: D001059:Apoproteins / Q000737:chemistry; D004298:Dopamine / Q000737:chemistry / Q000378:metabolism; D004795:Enzyme Stability / Q000187:drug effects; D004837:Epinephrine / Q000737:chemistry / Q000378:metabolism; D019791:Guanidine / Q000494:pharmacology; D006801:Humans; D007545:Isoproterenol / Q000494:pharmacology; D008024:Ligands; D008958:Models, Molecular; D050505:Mutant Proteins / Q000737:chemistry / Q000378:metabolism; D009154:Mutation / Q000235:genetics*; D011485:Protein Binding / Q000187:drug effects; D055503:Protein Multimerization / Q000187:drug effects; D020836:Protein Structure, Quaternary; D058767:Protein Unfolding / Q000187:drug effects; D011994:Recombinant Proteins / Q000737:chemistry; D053838:Scattering, Small Angle; D013482:Superoxide Dismutase / Q000737:chemistry* / Q000235:genetics* / Q000378:metabolism; D000072105:Superoxide Dismutase-1; D014529:Uridine / Q000031:analogs & derivatives / Q000494:pharmacology; D014961:X-Ray Diffraction
chemical_list: D001059:Apoproteins; D008024:Ligands; D050505:Mutant Proteins; D011994:Recombinant Proteins; C000606290:SOD1 protein, human; C001943:5-fluorouridine; D013482:Superoxide Dismutase; D000072105:Superoxide Dismutase-1; D019791:Guanidine; D007545:Isoproterenol; D004298:Dopamine; D014529:Uridine; D004837:Epinephrine