Self-oligomerization regulates stability of survival motor neuron protein isoforms by sequestering an SCFSlmb degron. Mol Biol Cell 2018 Jan 15;29(2):96-110
Date
11/24/2017Pubmed ID
29167380Pubmed Central ID
PMC5909936DOI
10.1091/mbc.E17-11-0627Scopus ID
2-s2.0-85040975387 (requires institutional sign-in at Scopus site) 17 CitationsAbstract
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.
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 AGAuthor
Allison D. Ebert PhD Associate Professor in the Cell Biology, Neurobiology and Anatomy department at Medical College of WisconsinMESH terms used to index this publication - Major topics in bold
AnimalsCells, Cultured
Disease Models, Animal
Drosophila
Drosophila Proteins
Homozygote
Humans
Mice
Motor Neurons
Muscular Atrophy, Spinal
Mutation, Missense
Nerve Tissue Proteins
Polymerization
RNA-Binding Proteins
Survival of Motor Neuron 1 Protein