Self-oligomerization regulates stability of Survival Motor Neuron (SMN) protein isoforms by sequestering an SCFSlmb degron
Kelsey M Gray,
Kevin A Kaifer,
Thomas R. Bonacci,
Allison D. Ebert,
Amanda C. Raimer,
Ashlyn M. Spring,
Sara ten Have,
Jacqueline J Glascock,
Gregory D Van Duyne,
Michael J. Emanuele,
Angus I Lamond,
Eric J Wagner,
Christian L Lorson,
A. Gregory Matera
Posted 30 Sep 2016
bioRxiv DOI: 10.1101/078337 (published DOI: 10.1091/mbc.E17-11-0627)
Posted 30 Sep 2016
Spinal muscular atrophy (SMA) is caused by homozygous mutations in human SMN1 (survival motor neuron 1). 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 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 conserved phospho-degron embedded within the human and fruitfly SMN YG-box self-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 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 largely exposed when SMN is monomeric, and sequestered when SMN forms higher-order multimers.
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