Dilysine motifs in exon 2b of SMN protein mediate binding to the COPI vesicle proteina α-COP and neurite outgrowth in a cell culture model of spinal muscular atrophy

Sara K. Custer, Adrian G. Todd, Natalia N. Singh, Elliot J. Androphy

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27 Scopus citations


Spinal muscular atrophy (SMA) is a devastating neuromuscular disorder that stems from low levels of survival of motor neuron (SMN) protein. The processes that cause motor neurons and muscle cells to become dysfunctional are incompletely understood.Weare interested inneuromuscularhomeostasisand the stresses putuponthat system by loss of SMN.We recently reported that α-COP, a member of the coatomer complex of coat protein I (COPI) vesicles, is an SMN-binding partner, implicating this protein complex in normal SMN function. To investigate the functional significance of the interaction between a-COP and SMN, we constructed an inducible NSC- 34 cell culture system to model the consequences of SMN depletion and find that depletion of SMN protein results in shortened neurites. Heterologous expression of human SMN, and interestingly over-expression of α-COP, restores normal neurite length and morphology. Mutagenesis of the canonical COPI dilysine motifs in exon 2b results in failure to bind to a-COP and abrogates the ability of human SMN to restore neurite outgrowth in SMN-depleted motor neuron-like NSC-34 cells. We conclude that the interaction between SMN and α-COP serves an important function in the growth and maintenance of motor neuron processes and may play a significant role in the pathogenesis of SMA.

Original languageEnglish (US)
Article numberddt254
Pages (from-to)4043-4052
Number of pages10
JournalHuman molecular genetics
Issue number20
StatePublished - Oct 1 2013


ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Genetics(clinical)

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