Self-oligomerization regulates stability of survival motor neuron protein isoforms by sequestering an SCFSlmb degron

Kelsey M. Gray, Kevin A. Kaifer, David Baillat, Ying Wen, Thomas R. Bonacci, Allison D. Ebert, Amanda C. Raimer, Ashlyn M. Spring, Sara ten Have, Jacqueline J. Glascock, Kushol Gupta, Gregory D. Van Duyne, Michael J. Emanuele, Angus I. Lamond, Eric J. Wagner, Christian L. Lorson, A. Gregory Matera (Lead / Corresponding author)

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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?7. Although SMN2 exon skipping is the principal contributor to SMA severity, mechanisms governing stability of survival motor neuron (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 phosphor 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?7. SMA-causing missense mutations that block multimerization of full-length SMN are also stabilized in the degron mutant background. Overexpression of SMN?7S270A, but not wild-type (WT) SMN?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.

Original languageEnglish
Pages (from-to)96-110
Number of pages15
JournalMolecular Biology of the Cell
Volume29
Issue number2
Early online date22 Nov 2017
DOIs
Publication statusPublished - 15 Jan 2018

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    Gray, K. M., Kaifer, K. A., Baillat, D., Wen, Y., Bonacci, T. R., Ebert, A. D., Raimer, A. C., Spring, A. M., Have, S. T., Glascock, J. J., Gupta, K., Van Duyne, G. D., Emanuele, M. J., Lamond, A. I., Wagner, E. J., Lorson, C. L., & Matera, A. G. (2018). Self-oligomerization regulates stability of survival motor neuron protein isoforms by sequestering an SCFSlmb degron. Molecular Biology of the Cell, 29(2), 96-110. https://doi.org/10.1091/mbc.E17-11-0627