Medical College of Wisconsin
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Self-oligomerization regulates stability of survival motor neuron protein isoforms by sequestering an SCF degron. Mol Biol Cell 2018 Jan 15;29(2):96-110 PMID: 29167380 PMCID: PMC5909936

Abstract

Spinal muscular atrophy (SMA) is caused by homozygous mutations in human  Expression of a duplicate gene () primarily results in skipping of exon 7 and production of an unstable protein isoform, SMNΔ7. Although  exon skipping is the principal contributor to SMA severity, mechanisms governing stability of survival motor neuron (SMN) isoforms are poorly understood. We used a  model system and label-free proteomics to identify the SCF ubiquitin E3 ligase complex as a novel SMN binding partner. SCF interacts with a phosphor degron embedded within the human and fruitfly SMN YG-box oligomerization domains. Substitution of a conserved serine (S270A) interferes with SCF 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 SMNΔ7, 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.

Author List

Gray KM, Kaifer KA, Baillat D, Wen Y, Bonacci TR, Ebert AD, Raimer AC, Spring AM, Have ST, Glascock JJ, Gupta K, Van Duyne GD, Emanuele MJ, Lamond AI, Wagner EJ, Lorson CL, Matera AG

Author

Allison D. Ebert PhD Assistant Professor in the Cell Biology, Neurobiology and Anatomy department at Medical College of Wisconsin



View this publication's entry at the Pubmed website PMID: 29167380
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