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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.

Self-oligomerization regulates stability of survival motor neuron protein isoforms by sequestering an SCFSlmb degron

Self-oligomerization regulates stability of survival motor neuron protein isoforms by sequestering an SCF^Slmb degron