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

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 SCF Slmb ubiquitin E3 ligase complex as a novel SMN binding partner. SCF Slmb interacts with a conserved phospho-degron embedded within the human and fruitfly SMN YG-box self-oligomerization domain. 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 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.