RT Journal Article
SR Electronic
T1 SCF<sup>Slmb</sup> recognizes a conserved degron within the survival motor neuron (SMN) self-interaction domain to mediate ubiquitylation of SMN and SMNΔ7 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 Thomas R. Bonacci
A1 Allison D. Ebert
A1 Amanda C. Raimer
A1 Ashlyn M. Spring
A1 Jacqueline J. Glascock
A1 Sara ten Have
A1 Michael J. Emanuele
A1 Angus I. Lamond
A1 Eric J. Wagner
A1 Christian L. Lorson
A1 A. Gregory Matera
YR 2017
UL http://biorxiv.org/content/early/2017/03/14/078337.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 isoform, called SMN∆7. 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. 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 selfoligomerization domain. Substitution of a conserved serine (S270A) interferes with SCFSlmb binding and 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 controlling functional activity.