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bioRxiv · 10.1101/078337

SCFSlmb recognizes a conserved degron within the survival motor neuron (SMN) self-interaction domain to mediate ubiquitylation of SMN and SMNΔ7 isoforms

Kelsey M Gray·Kevin A Kaifer·David Baillat·Ying Wen·Jacqueline J Glascock·Allison D Ebert·Sara ten Have·Angus I Lamond·Eric J Wagner·Christian L Lorson·A. Gregory Matera
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Abstract

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, SMN{Delta}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. SCFSlmb interacts with a phospho-degron embedded within the human and fruitfly SMN YG-box oligomerization domains. Substitution of a conserved serine (S270A) interferes with SCFSlmb binding and stabilizes SMN{Delta}7. SMA-causing missense mutations that block multimerization of full-length SMN are also stabilized in the degron mutant background. Overexpression of SMN{Delta}7S270A, but not wild-type SMN{Delta}7, 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.

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Kelsey M Gray, Kevin A Kaifer, David Baillat, Ying Wen, Jacqueline J Glascock, Allison D Ebert, Sara ten Have, Angus I Lamond, Eric J Wagner, Christian L Lorson, A. Gregory Matera. 2016-09-30. SCFSlmb recognizes a conserved degron within the survival motor neuron (SMN) self-interaction domain to mediate ubiquitylation of SMN and SMNΔ7 isoforms. https://doi.org/10.1101/078337

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