Faculty Collaboration Database

Self-oligomerization regulates stability of survival motor neuron protein isoforms by sequestering an SCF^Slmb degron. Mol Biol Cell 2018 Jan 15;29(2):96-110

Date

11/24/2017

Pubmed ID

29167380

Pubmed Central ID

PMC5909936

DOI

10.1091/mbc.E17-11-0627

Scopus ID

2-s2.0-85040975387 (requires institutional sign-in at Scopus site)   22 Citations

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 SCF^Slmb ubiquitin E3 ligase complex as a novel SMN binding partner. SCF^Slmb 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^Slmb 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^S270A, 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 Associate Professor in the Cell Biology, Neurobiology and Anatomy department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

Animals
Cells, 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