期刊
MOLECULAR CELL
卷 31, 期 2, 页码 244-254出版社
CELL PRESS
DOI: 10.1016/j.molcel.2008.06.004
关键词
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资金
- Howard Hughes Medical Institute Funding Source: Medline
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, a common motor neuron degenerative disease of severity commensurate with SMN levels and, correspondingly, snRNP assembly decreases. We developed a high-throughput screen for snRNP assembly modifiers and discovered that reactive oxygen species (ROS) inhibit SMN-complex activity in a dosedependent manner. ROS-generating compounds, e.g., the environmental toxins menadione and beta-lapachone (in vivo IC50 = 0.45 mu M) 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 an ROS target, suggesting that it may play a role in oxidative stress pathophysiology, which is associated with many degenerative diseases.
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