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, SMNΔ7. 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 SMNΔ7. SMA-causing missense mutations that block multimerization of full-length SMN are also stabilized in the degron mutant background. Overexpression of SMNΔ7S270A, but not wild-type (WT) SMNΔ7, 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.

journal_name

Mol Biol Cell

authors

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

doi

10.1091/mbc.E17-11-0627

subject

Has Abstract

pub_date

2018-01-15 00:00:00

pages

96-110

issue

2

eissn

1059-1524

issn

1939-4586

pii

mbc.E17-11-0627

journal_volume

29

pub_type

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