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Self-oligomerization regulates stability of Survival Motor Neuron (SMN) protein isoforms by sequestering an SCFSlmb degron

By Kelsey M Gray, Kevin A Kaifer, David Baillat, Ying Wen, Thomas R. Bonacci, Allison D. Ebert, Amanda C. Raimer, Ashlyn M. Spring, Sara ten Have, Jacqueline J Glascock, Kushol Gupta, 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)

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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