Self-oligomerization regulates stability of survival motor neuron protein isoforms by sequestering an SCF(Slmb) degron.
Self-oligomerization regulates stability of survival motor neuron protein isoforms by sequestering an SCF(Slmb) degron.
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DOI：
10.1091/mbc.e17-11-0627
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发表时间：
2018-01-15
影响因子：
3.3
通讯作者：
Matera AG
中科院分区：
文献类型：
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作者：
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
SMN蛋白水平与脊髓性肌萎缩的严重程度呈负相关。SCFSlmbE3连接酶复合物与嵌入在SMN c端自寡聚结构域内的脱粒相互作用。研究结果阐明了一个模型，即SMN度的可及性是由自多聚调节的。脊髓性肌萎缩症（SMA）是由人类SMN1的纯合突变引起的。重复基因（SMN2）的表达主要导致外显子7的跳跃和产生不稳定的蛋白质异构体SMNΔ7。虽然SMN2外显子跳跃是SMA严重程度的主要因素，但控制存活运动神经元（SMN）亚型稳定性的机制尚不清楚。我们使用果蝇模型系统和无标记蛋白质组学来鉴定SCFSlmb泛素E3连接酶复合物作为一种新的SMN结合伙伴。SCFSlmb与人类和果蝇SMN YG-box寡聚结构域内的磷光体降解子相互作用。取代一个保守丝氨酸（S270A）干扰SCFSlmb结合并稳定SMNΔ7。在退化突变背景下，阻断全长SMN多聚化的sma引起的错义突变也稳定下来。过表达SMNΔ7S270A，而不是野生型（WT） SMNΔ7，在SMA模型小鼠和人类运动神经元细胞培养系统中提供保护作用。我们的研究结果支持一个模型，其中当SMN是单体时，degron暴露，当SMN形成高阶多定时器时，degron被隔离。
SMN protein levels inversely correlate with the severity of spinal muscular atrophy. The SCFSlmbE3 ligase complex interacts with a degron embedded within the C-terminal self-oligomerization domain of SMN. The findings elucidate a model whereby accessibility of the SMN degron is regulated by self-multimerization. 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.