RT Journal Article SR Electronic T1 SCFSlmb recognizes a conserved degron within the survival motor neuron (SMN) self-interaction domain to mediate ubiquitylation of SMN and SMN∆7 isoforms JF bioRxiv FD Cold Spring Harbor Laboratory SP 078337 DO 10.1101/078337 A1 Kelsey M. Gray A1 Kevin A. Kaifer A1 David Baillat A1 Ying Wen A1 Jacqueline J. Glascock A1 Allison D. Ebert A1 Sara ten Have A1 Angus I. Lamond A1 Eric J. Wagner A1 Christian L. Lorson A1 A. Gregory Matera YR 2016 UL http://biorxiv.org/content/early/2016/09/30/078337.abstract AB Spinal muscular atrophy (SMA) is caused by homozygous loss of 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, called SMN∆7. Although SMN2 exon skipping is the principal contributor to SMA severity, mechanisms governing stability of SMN protein 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. We show that this interaction is conserved from fly to human, and that SCFSlmb interacts with a phospho-degron embedded within the SMN YG-box self- oligomerization domain. Substitution of a conserved serine (S270A) interferes with SCFSlmb binding and greatly stabilizes SMN∆7. SMA-causing missense mutations that block multimerization of full-length SMN are also stabilized in the degron mutant background. Furthermore, overexpression of SMN∆7S270A, but not wild-type SMN∆7, provides a protective effect in SMA model mice and human motor neuron cell culture systems. Our findings support a model wherein the SCFSlmb degron is largely exposed when SMN is monomeric, whereas it is sequestered when SMN forms higher-order multimers. SMN stability is thus regulated by self-oligomerization, providing an elegant mechanism for balancing functional activity.