PT  - JOURNAL ARTICLE
AU  - Kelsey M. Gray
AU  - Kevin A. Kaifer
AU  - David Baillat
AU  - Ying Wen
AU  - Thomas R. Bonacci
AU  - Allison D. Ebert
AU  - Amanda C. Raimer
AU  - Ashlyn M. Spring
AU  - Jacqueline J. Glascock
AU  - Sara ten Have
AU  - Michael J. Emanuele
AU  - Angus I. Lamond
AU  - Eric J. Wagner
AU  - Christian L. Lorson
AU  - A. Gregory Matera
TI  - Self-oligomerization regulates stability of Survival Motor Neuron (SMN) proteins by sequestering an SCF<sup>Slmb</sup> degron
AID  - 10.1101/078337
DP  - 2017 Jan 01
TA  - bioRxiv
PG  - 078337
4099  - http://biorxiv.org/content/early/2017/04/06/078337.short
4100  - http://biorxiv.org/content/early/2017/04/06/078337.full
AB  - 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 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 phospho-degron embedded within the human and fruitfly SMN YG-box oligomerization domain. 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 exposed when SMN is monomeric, and sequestered when SMN forms higher-order multimers.