SAP-ERASER - Targeted Protein Degradation using SAP effectors

SAP-ERASER - 使用 SAP 效应器进行靶向蛋白质降解

基本信息

  • 批准号:
    EP/X024415/1
  • 负责人:
  • 金额:
    $ 274.53万
  • 依托单位:
  • 依托单位国家:
    英国
  • 项目类别:
    Research Grant
  • 财政年份:
    2022
  • 资助国家:
    英国
  • 起止时间:
    2022 至 无数据
  • 项目状态:
    未结题

项目摘要

SAP-ERASER is an ambitious high-risk/high-gain program to deliver a radically novel Targeted Protein Degradation (TPD) technology. SAP effectors are secreted bacterial proteins that mediate the degradation of host transcription factors using different mechanisms. SAP05 effectors directly bind a 26S proteasome component leading to the degradation of protein substrates independently of E3 ligases and ubiquitination. SAP05 mode of action is unique because other proteolysis-targeting systems, such as PROTAC, depend on substrate ubiquitination and E3 ligases for proteasome-dependent degradation. SAP05 acts as a molecular glue that sandwiches a substrate and the 26S proteasome receptor RPN10 leading to efficient degradation of the substrate. Thus SAP05 offers the opportunity for a unique protein knock-down technology with many applications in biotechnology and biomedicine that complement existing gene knock-down tools, such as CRISPR-Cas and RNA interference. Here, I will combine biophysical, biochemical and genetic approaches to determine how SAP05 effectors selectively recruit proteins for degradation and to develop synthetic SAP05 variants with novel substrate binding specificities. I designed the project around three interconnected and complementary Work Packages (WPs), which are biophysics, substrate binding specificity and protein degradation technology. The gained knowledge will serve as a framework to develop the SAP-ERASER technology as an impactful targeted protein degradation tool for research, therapeutic and biotechnological applications in a variety of organisms, including humans, animals, yeast and plants.
SAP-ERASER是一项雄心勃勃的高风险/高收益计划,旨在提供一种全新的靶向蛋白质降解(TPD)技术。SAP效应子是分泌的细菌蛋白,其使用不同的机制介导宿主转录因子的降解。SAP 05效应子直接结合26 S蛋白酶体组分,导致蛋白质底物的降解,而不依赖于E3连接酶和泛素化。SAP 05的作用模式是独特的,因为其他蛋白水解靶向系统,如PROTAC,依赖于底物泛素化和E3连接酶的蛋白酶体依赖性降解。SAP 05作为一种分子胶,将底物和26 S蛋白酶体受体RPN 10夹在中间,导致底物的有效降解。因此,SAP 05为独特的蛋白质敲除技术提供了机会,该技术在生物技术和生物医学中具有许多应用,可补充现有的基因敲除工具,如CRISPR-Cas和RNA干扰。在这里,我将结合联合收割机生物物理,生物化学和遗传学的方法,以确定如何SAP 05效应器选择性地招募蛋白质降解,并开发合成SAP 05变体与新的底物结合特异性。我围绕三个相互关联和互补的工作包(WP)设计了这个项目,这三个工作包是生物物理学、底物结合特异性和蛋白质降解技术。所获得的知识将作为开发SAP-ERASER技术的框架,作为一种有效的靶向蛋白质降解工具,用于各种生物体的研究,治疗和生物技术应用,包括人类,动物,酵母和植物。

项目成果

期刊论文数量(3)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
Protein interaction mapping reveals widespread targeting of development-related host transcription factors by phytoplasma effectors
  • DOI:
    10.1111/tpj.16546
  • 发表时间:
    2023-11-15
  • 期刊:
  • 影响因子:
    7.2
  • 作者:
    Correa Marrero, Miguel;Capdevielle, Sylvain;Immink, Richard G. H.
  • 通讯作者:
    Immink, Richard G. H.
Bimodular architecture of bacterial effector SAP05 drives ubiquitin-independent targeted protein degradation
细菌效应器 SAP05 的双模块结构驱动不依赖于泛素的靶向蛋白质降解
  • DOI:
    10.1101/2023.06.19.545293
  • 发表时间:
    2023
  • 期刊:
  • 影响因子:
    0
  • 作者:
    Liu Q
  • 通讯作者:
    Liu Q
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Saskia Hogenhout其他文献

Saskia Hogenhout的其他文献

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{{ truncateString('Saskia Hogenhout', 18)}}的其他基金

All Aphid Effectors on DEK
DEK 上的所有蚜虫效应器
  • 批准号:
    BB/V008544/1
  • 财政年份:
    2021
  • 资助金额:
    $ 274.53万
  • 项目类别:
    Research Grant
Resistance: DNA methylation and the evolution of pesticide-resistance genes in aphids
抗性:蚜虫中 DNA 甲基化和农药抗性基因的进化
  • 批准号:
    BB/R009481/1
  • 财政年份:
    2018
  • 资助金额:
    $ 274.53万
  • 项目类别:
    Research Grant
Mechanisms involved in plant resistance to the green peach aphid Myzus persicae
植物对桃蚜 Myzus persicae 的抗性机制
  • 批准号:
    BB/N009169/1
  • 财政年份:
    2016
  • 资助金额:
    $ 274.53万
  • 项目类别:
    Research Grant
Functional Genomics of Aphid Adaptation to Plant Species
蚜虫适应植物物种的功能基因组学
  • 批准号:
    BB/L002108/1
  • 财政年份:
    2014
  • 资助金额:
    $ 274.53万
  • 项目类别:
    Research Grant
Dissecting phytoplasma effector adaptation to plant targets (Bilateral BBSRC-FAPESP application)
剖析植原体效应子对植物靶标的适应(双边 BBSRC-FAPESP 应用)
  • 批准号:
    BB/K002848/1
  • 财政年份:
    2013
  • 资助金额:
    $ 274.53万
  • 项目类别:
    Research Grant
Functional characterization of secreted proteins on the SAP11 region of the Aster Yellows phytoplasma strain Witches' Broom genome
紫菀黄植原体菌株女巫扫帚基因组 SAP11 区域分泌蛋白的功能表征
  • 批准号:
    BB/G001928/1
  • 财政年份:
    2008
  • 资助金额:
    $ 274.53万
  • 项目类别:
    Research Grant

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  • 批准号:
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