The cysteine-reactive small molecule ebselen facilitates effective SOD1 maturation
| العنوان: | The cysteine-reactive small molecule ebselen facilitates effective SOD1 maturation |
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| المؤلفون: | Enrico Luchinat, Paul M. O'Neill, Letizia Barbieri, Michael J. Capper, Lucia Banci, Gareth S. A. Wright, Svetlana V. Antonyuk, S. Samar Hasnain, Luke McAlary, Justin J. Yerbury, Eleonora Mercatelli |
| المساهمون: | Capper, Michael J., Wright, Gareth S. A., Barbieri, Letizia, Luchinat, Enrico, Mercatelli, Eleonora, McAlary, Luke, Yerbury, Justin J., O'Neill, Paul M., Antonyuk, Svetlana V., Banci, Lucia, Hasnain, S. Samar |
| المصدر: | Nature Communications, Vol 9, Iss 1, Pp 1-9 (2018) Nature Communications |
| بيانات النشر: | Nature Portfolio, 2018. |
| سنة النشر: | 2018 |
| مصطلحات موضوعية: | Azoles, 0301 basic medicine, Protein Folding, animal diseases, General Physics and Astronomy, Plasma protein binding, Isoindoles, Crystallography, X-Ray, Antioxidants, chemistry.chemical_compound, Superoxide Dismutase-1, 0302 clinical medicine, superoxide dismutase 1, neurodegenerative disease, Organoselenium Compounds, Edaravone, Disulfides, lcsh:Science, Multidisciplinary, biology, Protein Stability, Superoxide, in-cell NMR, SOD1, Small molecule, 3. Good health, superoxide dismutase 1, SOD1, ebselen, NMR, in-cell NMR, Amyotrophic Lateral Sclerosis, ALS, neurodegenerative disease, Protein Binding, Science, Article, General Biochemistry, Genetics and Molecular Biology, 03 medical and health sciences, Humans, Cysteine, Nuclear Magnetic Resonance, Biomolecular, Ebselen, Amyotrophic Lateral Sclerosis, nutritional and metabolic diseases, General Chemistry, HCCS, Asthma, NMR, nervous system diseases, HEK293 Cells, 030104 developmental biology, chemistry, nervous system, Chaperone (protein), Mutation, Biophysics, biology.protein, lcsh:Q, Protein Multimerization, ebselen, ALS, 030217 neurology & neurosurgery, Molecular Chaperones, Amyotrophic Lateral Sclerosi |
| الوصف: | Superoxide dismutase-1 (SOD1) mutants, including those with unaltered enzymatic activity, are known to cause amyotrophic lateral sclerosis (ALS). Several destabilizing factors contribute to pathogenicity including a reduced ability to complete the normal maturation process which comprises folding, metal cofactor acquisition, intra-subunit disulphide bond formation and dimerization. Immature SOD1 forms toxic oligomers and characteristic large insoluble aggregates within motor system cells. Here we report that the cysteine-reactive molecule ebselen efficiently confers the SOD1 intra-subunit disulphide and directs correct SOD1 folding, depopulating the globally unfolded precursor associated with aggregation and toxicity. Assisted formation of the unusual SOD1 cytosolic disulphide bond could have potential therapeutic applications. In less reducing environments, ebselen forms a selenylsulphide with Cys111 and restores the monomer–dimer equilibrium of A4V SOD1 to wild-type. Ebselen is therefore a potent bifunctional pharmacological chaperone for SOD1 that combines properties of the SOD1 chaperone hCCS and the recently licenced antioxidant drug, edaravone. Mutations in superoxide dismutase-1 (SOD1) cause amyotrophic lateral sclerosis (ALS). Here the authors present the SOD1 crystal structure bound to the small cysteine-reactive molecule ebselen and show that ebselen is a chaperone for SOD1. |
| وصف الملف: | ELETTRONICO |
| اللغة: | English |
| تدمد: | 2041-1723 |
| الوصول الحر: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::363b4e4bfd2f79989a5a66521344a803Test https://doaj.org/article/d39dd025e5674f268976de0edbd8107dTest |
| حقوق: | OPEN |
| رقم الانضمام: | edsair.doi.dedup.....363b4e4bfd2f79989a5a66521344a803 |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 20411723 |
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