Specificity of Plasmodium falciparum protein export
恶性疟原虫蛋白输出的特异性
基本信息
- 批准号:10632093
- 负责人:
- 金额:$ 19.46万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2022
- 资助国家:美国
- 起止时间:2022-06-01 至 2024-05-31
- 项目状态:已结题
- 来源:
- 关键词:AddressAdherenceAfrica South of the SaharaAlanineAspartic EndopeptidasesBiochemicalBiotinylationBrefeldin ACellsChildDevelopmentDiseaseElementsErythrocytesFutureImmune responseImmunoprecipitationImpairmentInterruptionInvestigationMalariaMass Spectrum AnalysisMediatingModelingMolecularMolecular ChaperonesMolecular ConformationMutationNutrientParasitesPathogenesisPathway interactionsPersonsPhenotypePlasmodium falciparumProcessProtein Export PathwayProteinsProteomicsReporterSpecificityStreptavidinSystemVacuoleVascular EndotheliumWorkbiophysical propertiescomparativeexperimental studyinsightknock-downmutantnovel therapeuticsplasmepsinpreventreverse geneticssecretory proteintherapeutic targetuptake
项目摘要
The malaria parasite Plasmodium falciparum exports several hundred
proteins into its host cell to modulate nutrient uptake, infected RBC biophysical
properties, adherence to vascular endothelium and host immune response. These
exported protein effectors are synthesized in the parasite ER, traverse the
secretory system and are then translocated from the parasitophorous vacuole (PV)
into the host RBC. Most have a protein export element (PEXEL) that is essential
for the export process but is cleaved co-translationally by the aspartic protease
plasmepsin V. How the processed protein is recognized for export is not at all clear.
Certain mutations in the mature N-terminus of PEXEL-containing reporter
constructs can prevent export, but changing the mature N-terminus to all alanines
does not impair export. We hypothesize that export is the default pathway for
secretory proteins and that specific mutations block export or promote PV retention.
We posit that these mutations dictate recognition by a chaperone. To establish this
model, we must identify the chaperone(s) that confer specificity.
To address these questions, Aim 1 will focus on the protein machinery that
mediates export specificity. Export-destined and PV retained proteins will be pulled
down from the PV and from the ER. Comparative proteomic analysis will be
employed to identify key components of the export pathway. Proximity biotinylation
will comprise a second approach to this analysis. Candidate interacting proteins
will be validated in reciprocal pulldowns. This will pave the way for future reverse
genetic and biochemical assessments. We anticipate that the proposed studies
will yield great insight into the mechanism of protein export that is so important to
the pathogenesis of malaria. We hope that this work will point the way to new
therapies for this devastating disease.
疟疾寄生虫恶性疟原虫出口数百
蛋白质进入宿主细胞调节营养吸收,感染红细胞生物物理
性质、对血管内皮细胞的黏附和宿主免疫反应。这些
输出的蛋白质效应器在寄生虫的内质网中合成,穿过
分泌系统,然后从寄生性液泡(PV)转移。
进入宿主红细胞。大多数都含有蛋白质输出元件(PEXEL),这是必不可少的
用于出口过程,但被天冬氨酸蛋白酶共翻译切割
纤溶酶V。加工后的蛋白质是如何被识别出口的,目前还完全不清楚。
含PEXEL报告基因成熟N端的某些突变
构造体可以阻止输出,但将成熟的N-末端更改为所有丙氨酸
不会损害出口。我们假设导出是
分泌蛋白和特定的突变阻止或促进光伏病毒的保留。
我们假设,这些突变决定了伴侣的识别。要确立这一点,
模型,我们必须确定赋予特异性的监护人(S)。
为了解决这些问题,目标1将重点放在蛋白质机制上
调解出口专用性。出口和光伏保留的蛋白质将被拉出
从PV和急诊室下来。比较蛋白质组学分析将是
用来确定出口途径的关键组成部分。邻位生物素化
将包括对这种分析的第二种方法。候选相互作用蛋白
将在互惠的下拉列表中进行验证。这将为未来的逆转铺平道路
遗传和生化评估。我们预期拟议的研究
将对蛋白质输出的机制有很大的洞察力,这对
疟疾的发病机制。我们希望这项工作将为新的
治疗这种毁灭性疾病的方法。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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Daniel E. Goldberg其他文献
Characterization of Membrane Contact Sites for the Facilitation of Lipid Exchange at the Malaria Parasite - Red Blood Cell Interface
- DOI:
10.1016/j.bpj.2019.11.3119 - 发表时间:
2020-02-07 - 期刊:
- 影响因子:
- 作者:
Matthias Garten;Josh Beck;Robyn Roth;John E. Heuser;Tatyana Tenkova-Heuser;Christopher K.E. Bleck;Daniel E. Goldberg;Joshua Zimmerberg - 通讯作者:
Joshua Zimmerberg
The structure of Ascaris hemoglobin domain I at 2.2 A resolution: molecular features of oxygen avidity.
2.2 A 分辨率下蛔虫血红蛋白结构域 I 的结构:氧亲合力的分子特征。
- DOI:
- 发表时间:
1995 - 期刊:
- 影响因子:11.1
- 作者:
Jian Yang;A. P. Kloek;Daniel E. Goldberg;F. Mathews - 通讯作者:
F. Mathews
When the Host Is Smarter Than the Parasite
当宿主比寄生虫更聪明时
- DOI:
- 发表时间:
2002 - 期刊:
- 影响因子:56.9
- 作者:
Daniel E. Goldberg - 通讯作者:
Daniel E. Goldberg
Malaria parasites require a divergent heme oxygenase for apicoplast gene expression and biogenesis
疟疾寄生虫需要不同的血红素加氧酶来进行顶质体基因表达和生物合成
- DOI:
- 发表时间:
2024 - 期刊:
- 影响因子:0
- 作者:
Amanda Mixon Blackwell;Y. Jami;Armiyaw S. Nasamu;S. Kudo;A. Senoo;Celine Slam;Kouhei Tsumoto;James A. Wohlschlegel;J. Caaveiro;Daniel E. Goldberg;P. Sigala - 通讯作者:
P. Sigala
ColE1 hybrid plasmids for Escherichia coli genes of glycolysis and the hexose monophosphate shunt
用于大肠杆菌糖酵解和己糖单磷酸分流基因的 ColE1 杂交质粒
- DOI:
10.1128/jb.137.1.502-506.1979 - 发表时间:
1979 - 期刊:
- 影响因子:3.2
- 作者:
Jennifer Thomson;T. P. D. Gerstenberger;Daniel E. Goldberg;Eva Gociar;Arminda Orozco DE Silva;D. Fraenkel - 通讯作者:
D. Fraenkel
Daniel E. Goldberg的其他文献
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{{ truncateString('Daniel E. Goldberg', 18)}}的其他基金
Defining the resistome in P. falciparum: evolution and mechanism
恶性疟原虫抗性组的定义:进化和机制
- 批准号:
10608899 - 财政年份:2022
- 资助金额:
$ 19.46万 - 项目类别:
Specificity of Plasmodium falciparum protein export
恶性疟原虫蛋白输出的特异性
- 批准号:
10508060 - 财政年份:2022
- 资助金额:
$ 19.46万 - 项目类别:
Structural Vaccinology and Design of Novel Imunogens for Malaria Vaccine Development
用于疟疾疫苗开发的结构疫苗学和新型免疫原设计
- 批准号:
10330551 - 财政年份:2018
- 资助金额:
$ 19.46万 - 项目类别:
Plasmepsin X function in Plasmodium
Plasmodium 中 Plasmepsin X 的功能
- 批准号:
10322714 - 财政年份:2018
- 资助金额:
$ 19.46万 - 项目类别:
IDENTIFICATION OF THE ANTIMALARIAL TARGET OF PEPSTATIN ESTERS
胃酶抑素酯抗疟靶点的鉴定
- 批准号:
8734676 - 财政年份:2014
- 资助金额:
$ 19.46万 - 项目类别:
ROLE OF PFHO-1 IN P. FALCIPARUM INTRAERYTHROCYTIC DEVELOPMENT
PFHO-1 在恶性疟原虫红细胞内发育中的作用
- 批准号:
8802857 - 财政年份:2014
- 资助金额:
$ 19.46万 - 项目类别:
ROLE OF PFHO-1 IN P. FALCIPARUM INTRAERYTHROCYTIC DEVELOPMENT
PFHO-1 在恶性疟原虫红细胞内发育中的作用
- 批准号:
8662416 - 财政年份:2014
- 资助金额:
$ 19.46万 - 项目类别:
IDENTIFICATION OF THE ANTIMALARIAL TARGET OF PEPSTATIN ESTERS
胃酶抑素酯抗疟靶点的鉴定
- 批准号:
8852545 - 财政年份:2014
- 资助金额:
$ 19.46万 - 项目类别:
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