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Citation
Gray, K.M., Kaifer, K.A., Baillat, D., Wen, Y., Bonacci, T.R., Ebert, A.D., Raimer, A.C., Spring, A.M., Have, S.T., Glascock, J.J., Gupta, K., Van Duyne, G.D., Emanuele, M.J., Lamond, A.I., Wagner, E.J., Lorson, C.L., Matera, A.G. (2018). Self-oligomerization regulates stability of survival motor neuron protein isoforms by sequestering an SCFSlmb degron.  Mol. Biol. Cell 29(2): 96--110.
FlyBase ID
FBrf0237738
Publication Type
Research paper
Abstract

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.

PubMed ID
PubMed Central ID
PMC5909936 (PMC) (EuropePMC)
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    Language of Publication
    English
    Additional Languages of Abstract
    Parent Publication
    Publication Type
    Journal
    Abbreviation
    Mol. Biol. Cell
    Title
    Molecular Biology of the Cell
    Publication Year
    1992-
    ISBN/ISSN
    1059-1524
    Data From Reference
    Alleles (8)
    Genes (25)
    Human Disease Models (1)
    Physical Interactions (14)
    Cell Lines (1)
    Natural transposons (1)
    Experimental Tools (1)
    Transgenic Constructs (6)