Format

Send to

Choose Destination
Mol Biol Cell. 2018 Jan 15;29(2):96-110. doi: 10.1091/mbc.E17-11-0627. Epub 2017 Nov 22.

Self-oligomerization regulates stability of survival motor neuron protein isoforms by sequestering an SCFSlmb degron.

Author information

1
Curriculum in Genetics and Molecular Biology and Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC 27599.
2
Integrative Program in Biological and Genome Sciences, Department of Biology and Department of Genetics, University of North Carolina, Chapel Hill, NC 27599.
3
Molecular Pathogenesis and Therapeutics Program, Department of Veterinary Pathobiology, College of Veterinary Medicine, University of Missouri, Columbia, MO 65211.
4
Department of Biochemistry and Molecular Biology, University of Texas Medical Branch, Galveston, TX 77550.
5
Department of Pharmacology, University of North Carolina, Chapel Hill, NC 27599.
6
Department of Cell Biology, Neurobiology and Anatomy, Medical College of Wisconsin, Milwaukee, WI 53226.
7
Centre for Gene Regulation and Expression, School of Life Sciences, University of Dundee, Dundee DD15EH, UK.
8
Department of Biochemistry and Biophysics, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104.
9
Curriculum in Genetics and Molecular Biology and Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC 27599 matera@unc.edu.

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.

PMID:
29167380
PMCID:
PMC5909936
DOI:
10.1091/mbc.E17-11-0627
[Indexed for MEDLINE]
Free PMC Article

Supplemental Content

Full text links

Icon for Atypon Icon for PubMed Central
Loading ...
Support Center