Inactivation of the SMN Complex by Oxidative Stress
| Autor: | Elizabeth Ottinger, Sungchan Cho, Lili Wan, Gideon Dreyfuss |
|---|---|
| Rok vydání: | 2008 |
| Předmět: |
Spliceosome
animal diseases Molecular Sequence Data Nerve Tissue Proteins Oxidative phosphorylation Biology medicine.disease_cause Article Small Molecule Libraries SMN complex SMN Complex Proteins medicine Humans snRNP Amino Acid Sequence Cysteine Disulfides Cyclic AMP Response Element-Binding Protein Molecular Biology Ribonucleoprotein RNA-Binding Proteins Cell Biology Spinal muscular atrophy Ribonucleoproteins Small Nuclear medicine.disease nervous system diseases Dithiothreitol Oxidative Stress Cross-Linking Reagents nervous system Biochemistry Reactive Oxygen Species Oxidation-Reduction Sequence Alignment Oxidative stress HeLa Cells Naphthoquinones |
| Zdroj: | Molecular Cell. 31:244-254 |
| ISSN: | 1097-2765 |
| DOI: | 10.1016/j.molcel.2008.06.004 |
| Popis: | The SMN complex is essential for the biogenesis of small nuclear ribonucleoproteins (snRNPs), the major constituents of the spliceosome. Deficiency in functional SMN protein causes spinal muscular atrophy (SMA), a common motor neuron degenerative disease of severity commensurate with SMN levels, and correspondingly, snRNP assembly decrease. We developed a high throughput screen for snRNP assembly modifiers and discovered that reactive oxygen species (ROS) inhibit SMN complex activity in a dose-dependent manner. ROS-generating compounds, e.g, the environmental toxins menadione and β-lapachone (in vivo IC50=0.45 μM) also cause intermolecular disulfide crosslinking of SMN. Both the oxidative inactivation and SMN crosslinking can be reversed by reductants. We identified two cysteines that form SMN-SMN disulfide crosslinks, defining specific contact points in oligomeric SMN. Thus, the SMN complex is a redox-sensitive assemblyosome and a novel ROS target, suggesting that it may play a role in oxidative stress pathophysiology, which is associated with many degenerative diseases. |
| Databáze: | OpenAIRE |
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