The Energetic Cost of Protein Retrotranslocation during ER-associated Degradation

内质网相关降解过程中蛋白质逆转位的能量消耗

基本信息

项目摘要

DESCRIPTION (provided by applicant): Approximately one-third of all newly synthesized proteins pass through the secretory pathway. These proteins use cues within their primary structure as well as a conserved chaperone system in order to fold into their native, functional conformations. When folding is disrupted, i.e. by an inherited genetic mutation, misfolded proteins are "sensed" by the cellular proteostasis machinery and may then be targeted for ER-associated degradation (ERAD). ERAD substrates have been classified based on the location of the folding lesion within their ER lumenal, membrane, or cytoplasmic domains. Specifically, it appears that an ERAD substrate can be recognized at different points during its synthesis depending on the location of the "folding lesion". Ste6p is an ABC transporter found in the yeast S. cerevisiae, and is required for export of the a-factor mating pheromone. Truncation of Ste6p's large C-terminal cytoplasmic domain (Ste6p*) converts the protein into a substrate for the ERAD-C (cytoplasmic) pathway. Because the mutation that renders Ste6p* into an ERAD substrate resides at the extreme C-terminus, the "decision" for degradation must occur post-translationally. Recent evidence from the Brodsky lab indicates that when the truncated C-terminus of Ste6p* is transferred to other proteins it is sufficient to induce the degradation of the chimera, raising the possibility that the sequence can act as a "degron" to target proteins for degradation. I propose to dissect the ERAD pathway taken by chimeric proteins containing the Ste6p* degron. The first goal of this research is to determine the chaperones, ubiquitination machinery, and requirements for retrotranslocation for an ERAD substrate with a post-translational ERAD-C-type lesion. Second, since little is known about how integral membrane hydrophobicity influences ERAD efficiency, I propose to generate chimeric constructs including the Ste6p* degron with varied transmembrane domains. The goal of these studies is to determine if the difference in transmembrane hydrophobicity of an ERAD substrate correlates with degradation and/or membrane extraction efficiency. These studies will help to extend our knowledge of the complex mechanisms used by cells to degrade misfolded proteins, identify new factors that catalyze ERAD, and identify potential drug targets for disease-associated ERAD substrates.
描述(由申请人提供):所有新合成的蛋白质中约有三分之一通过分泌途径。这些蛋白质在其一级结构中使用线索以及保守的伴侣系统,以便折叠成其天然的功能构象。当折叠被破坏时,即通过遗传性基因突变,错误折叠的蛋白质被细胞蛋白质稳定机制“感知”,然后可以靶向ER相关降解(ERAD)。ERAD底物已根据其ER内腔、膜或胞质结构域内折叠病变的位置进行分类。具体而言,似乎ERAD底物可以在其合成过程中的不同点被识别,这取决于“折叠损伤”的位置。Step 6p是在酵母S.酿酒酵母,并且是输出a因子交配信息素所必需的。截短Ste 6p的大C末端胞质结构域(Ste 6p *)将蛋白质转化为ERAD-C(胞质)途径的底物。由于使Ste 6p * 成为ERAD底物的突变位于最末端的C-末端,因此降解的“决定”必须在降解后发生。来自Brodsky实验室的最新证据表明,当Ste 6p * 的截短C末端转移到其他蛋白质时,足以诱导嵌合体的降解,从而提高了该序列可以作为“降解决定子”以靶向蛋白质进行降解的可能性。我建议解剖ERAD途径所采取的嵌合蛋白含有的Ste 6p * 降解决定子。本研究的第一个目标是确定伴侣,泛素化机制,并要求ERAD底物与翻译后ERAD-C型病变的逆转录。第二,由于很少有人知道如何完整的膜疏水性影响ERAD效率,我建议产生嵌合结构,包括不同的跨膜结构域的Ste 6p * 降解决定子。这些研究的目标是确定ERAD底物的跨膜疏水性差异是否与降解和/或膜提取效率相关。这些研究将有助于扩展我们对细胞降解错误折叠蛋白质的复杂机制的了解,确定催化ERAD的新因素,并确定疾病相关ERAD底物的潜在药物靶点。

项目成果

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Christopher James Guerriero其他文献

Christopher James Guerriero的其他文献

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{{ truncateString('Christopher James Guerriero', 18)}}的其他基金

Developing a new platform to characterize and treat disease-associated polycystin variants
开发一个新平台来表征和治疗与疾病相关的多囊蛋白变体
  • 批准号:
    10726754
  • 财政年份:
    2023
  • 资助金额:
    $ 2.7万
  • 项目类别:
Proteostatic regulation of disease-causing polycystin 2 variants
致病多囊蛋白 2 变体的蛋白抑制调节
  • 批准号:
    10092157
  • 财政年份:
    2020
  • 资助金额:
    $ 2.7万
  • 项目类别:
Experimental and Computational Modeling of ERAD Substrate Retrotranslocation
ERAD 底物逆转位的实验和计算模型
  • 批准号:
    9271181
  • 财政年份:
    2014
  • 资助金额:
    $ 2.7万
  • 项目类别:
Experimental and Computational Modeling of ERAD Substrate Retrotranslocation
ERAD 底物逆转位的实验和计算模型
  • 批准号:
    8677120
  • 财政年份:
    2014
  • 资助金额:
    $ 2.7万
  • 项目类别:
The Energetic Cost of Protein Retrotranslocation during ER-associated Degradation
内质网相关降解过程中蛋白质逆转位的能量消耗
  • 批准号:
    7801761
  • 财政年份:
    2010
  • 资助金额:
    $ 2.7万
  • 项目类别:
The Energetic Cost of Protein Retrotranslocation during ER-associated Degradation
内质网相关降解过程中蛋白质逆转位的能量消耗
  • 批准号:
    8089423
  • 财政年份:
    2010
  • 资助金额:
    $ 2.7万
  • 项目类别:
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