@article {Gray078337, author = {Kelsey M. Gray and Kevin A. Kaifer and David Baillat and Ying Wen and Thomas R. Bonacci and Allison D. Ebert and Amanda C. Raimer and Ashlyn M. Spring and Jacqueline J. Glascock and Sara ten Have and Michael J. Emanuele and Angus I. Lamond and Eric J. Wagner and Christian L. Lorson and A. Gregory Matera}, title = {SCFSlmb recognizes a conserved degron within the survival motor neuron (SMN) self-interaction domain to mediate ubiquitylation of SMN and SMNΔ7 isoforms}, elocation-id = {078337}, year = {2017}, doi = {10.1101/078337}, publisher = {Cold Spring Harbor Laboratory}, abstract = {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 {\textquoteleft}label-free{\textquoteright} 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.}, URL = {https://www.biorxiv.org/content/early/2017/03/14/078337}, eprint = {https://www.biorxiv.org/content/early/2017/03/14/078337.full.pdf}, journal = {bioRxiv} }