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Actinfilin: Linking synaptic proteins to the ubiquitin-proteasome pathway.

机译:肌动蛋白:将突触蛋白连接到泛素-蛋白酶体途径。

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摘要

Actinfilin, a brain-specific protein characterized by an N-terminal BTB/POZ domain followed by six Kelch domain repeats, has previously been found to interact with the actin cytoskeleton. However, no defined role for actinfilin has been established in the brain. In the research presented here, we show that actinfilin, as a member of the BTB/POZ-Kelch protein family, links synaptic substrates with Cul3 and the ubiquitinproteasome pathway. We identify two such actinfilin substrates: GluR6 and Shank. GluR6, as a subunit of the kainate subtype of glutamate receptors, is a major mediator for neural excitation. The Kelch domain region of actinfilin binds GluR6 at a hydrophobic amino acid stretch proximal to its C-terminus. Upon binding, actinfilin targets GluR6 for degradation via Cul3 and the ubiquitin-proteasome pathway. GluR6 ubiquitination and degradation can be decreased by disrupting the ubiquitination pathway or the actinfilin/GluR6 interaction. Mice with lowered neuronal Cul3 expression have elevated levels of synaptic GluR6, but other subtypes of ionotropic glutamate receptors are not changed. Lowering actinfilin levels in dissociated hippocampal cultures with RNAi causes a significant increase in dendritic spine density, which may be due to an increase in the levels of Shank, a postsynaptic scaffolding protein. Actinfilin binds Shank in heterologous cell culture as well as in rat cerebellar extracts. Mice with lowered Cul3 expression have altered expression of many scaffolding proteins in their synapses, including elevated synaptic levels of Shank. These studies are the first to show that kainate receptors are ubiquitinated, and reveal a potential mechanism in regulation of the mammalian synapse.
机译:肌动蛋白是一种脑特异性蛋白,其特征是N端BTB / POZ结构域,然后是六个Kelch结构域重复序列,先前已发现与肌动蛋白细胞骨架相互作用。但是,尚未在脑中确定肌动蛋白的明确作用。在这里提出的研究中,我们表明肌动蛋白作为BTB / POZ-Kelch蛋白家族的成员,将突触底物与Cul3和泛素蛋白酶体途径联系起来。我们确定了两个这样的肌动蛋白底物:GluR6和小腿。 GluR6,作为谷氨酸受体的红藻氨酸亚型的一个亚基,是神经兴奋的主要介质。肌动蛋白的Kelch结构域区域在靠近其C端的疏水氨基酸处结合GluR6。结合后,肌动蛋白丝蛋白靶向GluR6通过Cul3和泛素-蛋白酶体途径降解。 GluR6泛素化和降解可以通过破坏泛素化途径或肌动蛋白/ GluR6相互作用来减少。神经元Cul3表达降低的小鼠突触GluR6水平升高,但离子型谷氨酸受体的其他亚型没有改变。使用RNAi降低海马分离培养物中肌动蛋白的水平会导致树突棘密度显着增加,这可能是由于突触后支架蛋白Shank的水平增加所致。肌动蛋白在异源细胞培养物中以及在大鼠小脑提取物中与Shank结合。具有降低的Cul3表达的小鼠已经改变了许多突触中支架蛋白的表达,包括升高的Shank突触水平。这些研究首次显示出海藻酸盐受体被泛素化,并揭示了调节哺乳动物突触的潜在机制。

著录项

  • 作者

    Salinas, Gregory D.;

  • 作者单位

    Brown University.;

  • 授予单位 Brown University.;
  • 学科 Biology Neuroscience.; Biology Cell.
  • 学位 Ph.D.
  • 年度 2007
  • 页码 141 p.
  • 总页数 141
  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类 神经科学;细胞生物学;
  • 关键词

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