Regulation of SMN protein stability

Barrington G. Burnett, Eric Muñoz, Animesh Tandon, Deborah Y. Kwon, Charlotte Sumner, Kenneth H. Fischbeck

Research output: Contribution to journalArticle

Abstract

Spinal muscular atrophy (SMA) is caused by mutations of the survival of motor neuron (SMN1) gene and deficiency of full-length SMN protein (FL-SMN). All SMA patients retain one or more copies of the SMN2 gene, but the principal protein product of SMN2 lacks exon 7 (SMNΔ7) and is unable to compensate for a deficiency of FL-SMN. SMN is known to oligomerize and form a multimeric protein complex; however, the mechanisms regulating stability and degradation of FL-SMN and SMNΔ7 proteins have been largely unexplored. Using pulsechase analysis, we characterized SMN protein turnover and confirmed that SMN was ubiquitinated and degraded by the ubiquitin proteasome system (UPS). The SMNΔ7 protein had a twofold shorter half-life than FL-SMN in cells despite similar intrinsic rates of turnover by the UPS in a cell-free assay. Mutations that inhibited SMN oligomerization and complex formation reduced the FL-SMN half-life. Furthermore, recruitment of SMN into large macromolecular complexes as well as increased association with several Gemin proteins was regulated in part by protein kinase A. Together, our data indicate that SMN protein stability is modulated by complex formation. Promotion of the SMN complex formation may be an important novel therapeutic strategy for SMA.

Original languageEnglish (US)
Pages (from-to)1107-1115
Number of pages9
JournalMolecular and Cellular Biology
Volume29
Issue number5
DOIs
StatePublished - Mar 2009

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Protein Stability
SMN Complex Proteins
Proteins
Spinal Muscular Atrophy
Proteasome Endopeptidase Complex
Ubiquitin
Half-Life
Macromolecular Substances
Mutation
Motor Neurons
Cyclic AMP-Dependent Protein Kinases
Exons

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

Cite this

Burnett, B. G., Muñoz, E., Tandon, A., Kwon, D. Y., Sumner, C., & Fischbeck, K. H. (2009). Regulation of SMN protein stability. Molecular and Cellular Biology, 29(5), 1107-1115. https://doi.org/10.1128/MCB.01262-08

Regulation of SMN protein stability. / Burnett, Barrington G.; Muñoz, Eric; Tandon, Animesh; Kwon, Deborah Y.; Sumner, Charlotte; Fischbeck, Kenneth H.

In: Molecular and Cellular Biology, Vol. 29, No. 5, 03.2009, p. 1107-1115.

Research output: Contribution to journalArticle

Burnett, BG, Muñoz, E, Tandon, A, Kwon, DY, Sumner, C & Fischbeck, KH 2009, 'Regulation of SMN protein stability', Molecular and Cellular Biology, vol. 29, no. 5, pp. 1107-1115. https://doi.org/10.1128/MCB.01262-08
Burnett BG, Muñoz E, Tandon A, Kwon DY, Sumner C, Fischbeck KH. Regulation of SMN protein stability. Molecular and Cellular Biology. 2009 Mar;29(5):1107-1115. https://doi.org/10.1128/MCB.01262-08
Burnett, Barrington G. ; Muñoz, Eric ; Tandon, Animesh ; Kwon, Deborah Y. ; Sumner, Charlotte ; Fischbeck, Kenneth H. / Regulation of SMN protein stability. In: Molecular and Cellular Biology. 2009 ; Vol. 29, No. 5. pp. 1107-1115.
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