Self-oligomerization regulates stability of survival motor neuron protein isoforms by sequestering an SCFSlmb degron.
نویسندگان
چکیده
Spinal muscular atrophy (SMA) is caused by homozygous mutations in human SMN1 Expression of a duplicate gene (SMN2) primarily results in skipping of exon 7 and production of an unstable protein isoform, SMNΔ7. Although SMN2 exon skipping is the principal contributor to SMA severity, mechanisms governing stability of survival motor neuron (SMN) isoforms are poorly understood. We used a Drosophila model system and label-free proteomics to identify the SCFSlmb ubiquitin E3 ligase complex as a novel SMN binding partner. SCFSlmb interacts with a phosphor degron embedded within the human and fruitfly SMN YG-box oligomerization domains. Substitution of a conserved serine (S270A) interferes with SCFSlmb binding and stabilizes SMNΔ7. SMA-causing missense mutations that block multimerization of full-length SMN are also stabilized in the degron mutant background. Overexpression of SMNΔ7S270A, but not wild-type (WT) SMNΔ7, provides a protective effect in SMA model mice and human motor neuron cell culture systems. Our findings support a model wherein the degron is exposed when SMN is monomeric and sequestered when SMN forms higher-order multimers.
منابع مشابه
Self-oligomerization regulates stability of Survival Motor Neuron (SMN) protein isoforms by sequestering an SCFSlmb degron
Curriculum in Genetics and Molecular Biology and Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC 27599, USA Integrative Program in Biological and Genome Sciences, Department of Biology and Department of Genetics, University of North Carolina, Chapel Hill, NC 27599, USA Molecular Pathogenesis and Therapeutics Program, Department of Veterinary Pathobiology, C...
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ورودعنوان ژورنال:
- Molecular biology of the cell
دوره 29 2 شماره
صفحات -
تاریخ انتشار 2018