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

Abstract

Spinal muscular atrophy (SMA) is caused by homozygous mutations in human <i>SMN1</i> Expression of a duplicate gene (<i>SMN2</i>) primarily results in skipping of exon 7 and production of an unstable protein isoform, SMNΔ7. Although <i>SMN2</i> exon skipping is the principal contributor to SMA severity, mechanisms governing stability of survival motor neuron (SMN) isoforms are poorly understood. We used a <i>Drosophila</i> 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.