title: Regulation of SMN protein stability.
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 (SMNDelta7) 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 SMNDelta7 proteins have been largely unexplored. Using pulse-chase analysis, we characterized SMN protein turnover and confirmed that SMN was ubiquitinated and degraded by the ubiquitin proteasome system (UPS). The SMNDelta7 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.
authors.affiliation: Neurogenetics Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD 20892, USA. burnettb@ninds.nih.gov
authors.forename: Barrington G
authors.initials: BG
authors.lastname: Burnett
authors.forename: Eric
authors.initials: E
authors.lastname: Muñoz
authors.forename: Animesh
authors.initials: A
authors.lastname: Tandon
authors.forename: Deborah Y
authors.initials: DY
authors.lastname: Kwon
authors.forename: Charlotte J
authors.initials: CJ
authors.lastname: Sumner
authors.forename: Kenneth H
authors.initials: KH
authors.lastname: Fischbeck
mesh_terms: D019281:Dimerization; D006207:Half-Life; D006801:Humans; D046912:Multiprotein Complexes; D009154:Mutation; D046988:Proteasome Endopeptidase Complex; D055550:Protein Stability; D055533:Survival of Motor Neuron 1 Protein / Q000235:genetics / Q000378:metabolism*; D054875:Ubiquitination
chemical_list: D046912:Multiprotein Complexes; D055533:Survival of Motor Neuron 1 Protein; D046988:Proteasome Endopeptidase Complex