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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Motor Neurons
Protein Isoforms
Spinal Muscular Atrophy
Exons
Duplicate Genes
Ubiquitin-Protein Ligases
Missense Mutation
Proteomics
Serine
Drosophila
Cell Culture Techniques
Mutation

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Gray, K. M., Kaifer, K. A., Baillat, D., Wen, Y., Bonacci, T. R., Ebert, A. D., ... 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
Gray, Kelsey M. ; Kaifer, Kevin A. ; Baillat, David ; Wen, Ying ; Bonacci, Thomas R. ; Ebert, Allison D. ; Raimer, Amanda C. ; Spring, Ashlyn M. ; Have, Sara ten ; Glascock, Jacqueline J. ; Gupta, Kushol ; Van Duyne, Gregory D. ; Emanuele, Michael J. ; Lamond, Angus I. ; Wagner, Eric J. ; Lorson, Christian L. ; Matera, A. Gregory. / Self-oligomerization regulates stability of survival motor neuron protein isoforms by sequestering an SCFSlmb degron. In: Molecular Biology of the Cell. 2018 ; Vol. 29, No. 2. pp. 96-110.
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title = "Self-oligomerization regulates stability of survival motor neuron protein isoforms by sequestering an SCFSlmb degron",
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.",
author = "Gray, {Kelsey M.} and Kaifer, {Kevin A.} and David Baillat and Ying Wen and Bonacci, {Thomas R.} and Ebert, {Allison D.} and Raimer, {Amanda C.} and Spring, {Ashlyn M.} and Have, {Sara ten} and Glascock, {Jacqueline J.} and Kushol Gupta and {Van Duyne}, {Gregory D.} and Emanuele, {Michael J.} and Lamond, {Angus I.} and Wagner, {Eric J.} and Lorson, {Christian L.} and Matera, {A. Gregory}",
note = "This work was supported by NIGMS R01-GM118636 (to A.G.M.). K.M.G. was supported by graduate research fellowship DGE-1144081 from the NSF. Work in the Wagner lab (D.B and E.J.W.) was supported by the Welch Foundation (H1889).",
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Gray, KM, Kaifer, KA, Baillat, D, Wen, Y, Bonacci, TR, Ebert, AD, Raimer, AC, Spring, AM, Have, ST, Glascock, JJ, Gupta, K, Van Duyne, GD, Emanuele, MJ, Lamond, AI, Wagner, EJ, Lorson, CL & Matera, AG 2018, 'Self-oligomerization regulates stability of survival motor neuron protein isoforms by sequestering an SCFSlmb degron', Molecular Biology of the Cell, vol. 29, no. 2, pp. 96-110. https://doi.org/10.1091/mbc.E17-11-0627

Self-oligomerization regulates stability of survival motor neuron protein isoforms by sequestering an SCFSlmb degron. / Gray, Kelsey M.; Kaifer, Kevin A.; Baillat, David; Wen, Ying; Bonacci, Thomas R.; Ebert, Allison D.; Raimer, Amanda C.; Spring, Ashlyn M.; Have, Sara ten; Glascock, Jacqueline J.; Gupta, Kushol; Van Duyne, Gregory D.; Emanuele, Michael J.; Lamond, Angus I.; Wagner, Eric J.; Lorson, Christian L.; Matera, A. Gregory (Lead / Corresponding author).

In: Molecular Biology of the Cell, Vol. 29, No. 2, 15.01.2018, p. 96-110.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Self-oligomerization regulates stability of survival motor neuron protein isoforms by sequestering an SCFSlmb degron

AU - Gray, Kelsey M.

AU - Kaifer, Kevin A.

AU - Baillat, David

AU - Wen, Ying

AU - Bonacci, Thomas R.

AU - Ebert, Allison D.

AU - Raimer, Amanda C.

AU - Spring, Ashlyn M.

AU - Have, Sara ten

AU - Glascock, Jacqueline J.

AU - Gupta, Kushol

AU - Van Duyne, Gregory D.

AU - Emanuele, Michael J.

AU - Lamond, Angus I.

AU - Wagner, Eric J.

AU - Lorson, Christian L.

AU - Matera, A. Gregory

N1 - This work was supported by NIGMS R01-GM118636 (to A.G.M.). K.M.G. was supported by graduate research fellowship DGE-1144081 from the NSF. Work in the Wagner lab (D.B and E.J.W.) was supported by the Welch Foundation (H1889).

PY - 2018/1/15

Y1 - 2018/1/15

N2 - 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.

AB - 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.

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U2 - 10.1091/mbc.E17-11-0627

DO - 10.1091/mbc.E17-11-0627

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EP - 110

JO - Molecular Biology of the Cell

JF - Molecular Biology of the Cell

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