Structural Basis for Translation Initiation in Leishmania Major

大利什曼原虫翻译起始的结构基础

基本信息

  • 批准号:
    10373100
  • 负责人:
  • 金额:
    $ 25.4万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2021
  • 资助国家:
    美国
  • 起止时间:
    2021-03-16 至 2023-08-31
  • 项目状态:
    已结题

项目摘要

ABSTRACT About 20 species of the protozoan parasite Leishmania are distributed across the globe and cause roughly 1 million new cases of leishmaniasis annually. The most severe form of leishmaniasis (e.g., kala-azar or visceral leishmaniasis) is lethal if untreated. Few therapies are available, and significant side effects and parasite resistance limit their effectiveness. The World Health Organization lists Leishmaniasis as a neglected tropical disease for which the development of new treatments is a high priority. Most of the gene expression in Leishmania is regulated at the level of translation. In mammalian cells, translation initiation is well characterized. A crucial step in this process includes the recognition by eIF4E, a cap-binding protein, of an m7GTP moiety located at the 5’ end of messenger RNAs (mRNAs). eIF4E, through its interaction with other translation initiation factors, ultimately coordinates the recruitment of the small ribosomal subunit. To date, six Leishmania mRNA cap-binding protein isoforms (LIF4E-1 through -6) have been identified. The Leishmania mRNA cap structure is unique and consists of the eukaryotic m7GTP cap followed by four nucleotides that are hypermethylated (“cap-4”). A conserved mini-exon spliced leader RNA (SL RNA) of 39 nucleotides is also added to each transcript through trans-splicing. We previously determined the X-ray crystal structure of LIF4E-1, the only cap-binding isoform that is expressed in Leishmania amastigotes (human infective stage), bound to an interacting partner that represses its cap-binding activity (L4E-IP1). LIF4E-1 was also recently shown to interact directly with the subunit “a” of Leishmania initiation factor 3 (LIF3), a large (~ 800 kDa) multiprotein complex that binds the small ribosomal subunit. An interaction between an IF4E cap-binding protein and an IF3 subunit has never been observed in other systems, and the details of the LIF4E-1/LIF3a molecular interaction are unknown. We hypothesize that a LIF4E-1/cap-4 SL RNA/LIF3a interaction influences the organization of LIF3 and how it assembles a competent pre-initiation complex (PIC) in amastigotes. The LIF4E-1/LIF3a interaction would bypass the need for an eIF4G-like scaffolding protein. In this proposal, we will pursue two specific aims: 1) To define the molecular basis for LIF3a interaction with the cap-binding protein LIF4E-1. 2) To determine a high-resolution cryo-EM structure of LIF4E-1/cap-4 SL RNA bound to LIF3a or assembled with LIF3 on the small ribosomal subunit. Our work will reveal the molecular basis for unique protein- protein interactions in Leishmania parasites, and this information, in turn, could guide the development of specific translation initiation inhibitors against these parasites.
抽象的 大约 20 种原生动物寄生虫利什曼原虫分布在全球各地并引起 每年大约有 100 万新利什曼病病例。最严重的利什曼病(例如黑热病或黑热病) 内脏利什曼病)如果不治疗的话是致命的。可用的治疗方法很少,且副作用和寄生虫显着 阻力限制了它​​们的有效性。世界卫生组织将利什曼病列为被忽视的热带病 开发新疗法是当务之急的疾病。大部分基因表达于 利什曼原虫在翻译层面受到监管。在哺乳动物细胞中,翻译起始已得到充分表征。 此过程中的一个关键步骤包括 eIF4E(一种帽子结合蛋白)对 m7GTP 部分的识别 位于信使 RNA (mRNA) 的 5' 端。 eIF4E,通过与其他翻译起始的相互作用 因素,最终协调小核糖体亚基的招募。 迄今为止,已鉴定出六种利什曼原虫 mRNA 帽结合蛋白亚型(LIF4E-1 至 -6)。 利什曼原虫 mRNA 帽结构是独特的,由真核 m7GTP 帽和后面的四个组成 高度甲基化的核苷酸(“cap-4”)。保守的迷你外显子剪接前导 RNA (SL RNA) 为 39 核苷酸也通过转拼添加到每个转录物中。我们之前确定了X射线晶体 LIF4E-1 的结构,是在利什曼原虫无鞭毛体(人类感染性 阶段),与抑制其帽结合活性(L4E-IP1)的相互作用伙伴结合。 LIF4E-1 也被 最近显示与利什曼原虫起始因子 3 (LIF3) 的亚基“a”直接相互作用,LIF3 是一个大的 (~ 800 kDa) 结合小核糖体亚基的多蛋白复合物。 IF4E 帽结合蛋白之间的相互作用 并且在其他系统中从未观察到过 IF3 亚基,并且 LIF4E-1/LIF3a 分子的详细信息 相互作用未知。我们假设 LIF4E-1/cap-4 SL RNA/LIF3a 相互作用影响 LIF3 的组织以及它如何在无鞭毛体中组装有效的预起始复合物 (PIC)。这 LIF4E-1/LIF3a 相互作用将绕过对 eIF4G 样支架蛋白的需要。在本提案中,我们将 追求两个具体目标:1) 定义 LIF3a 与帽结合蛋白相互作用的分子基础 LIF4E-1。 2) 确定与 LIF3a 或 LIF4E-1/cap-4 SL RNA 结合的高分辨率冷冻电镜结构 在小核糖体亚基上与 LIF3 组装。我们的工作将揭示独特蛋白质的分子基础 利什曼原虫寄生虫中的蛋白质相互作用,而这些信息反过来可以指导特定的发展 针对这些寄生虫的翻译起始抑制剂。

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)

数据更新时间:{{ journalArticles.updateTime }}

{{ item.title }}
{{ item.translation_title }}
  • DOI:
    {{ item.doi }}
  • 发表时间:
    {{ item.publish_year }}
  • 期刊:
  • 影响因子:
    {{ item.factor }}
  • 作者:
    {{ item.authors }}
  • 通讯作者:
    {{ item.author }}

数据更新时间:{{ journalArticles.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ monograph.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ sciAawards.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ conferencePapers.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ patent.updateTime }}

Melissa Leger-Abraham其他文献

Melissa Leger-Abraham的其他文献

{{ item.title }}
{{ item.translation_title }}
  • DOI:
    {{ item.doi }}
  • 发表时间:
    {{ item.publish_year }}
  • 期刊:
  • 影响因子:
    {{ item.factor }}
  • 作者:
    {{ item.authors }}
  • 通讯作者:
    {{ item.author }}

{{ truncateString('Melissa Leger-Abraham', 18)}}的其他基金

Ribosome structure determination from Apicomplexan parasites
顶复门寄生虫的核糖体结构测定
  • 批准号:
    10726704
  • 财政年份:
    2023
  • 资助金额:
    $ 25.4万
  • 项目类别:
Structural Basis for Translation Initiation in Leishmania Major
大利什曼原虫翻译起始的结构基础
  • 批准号:
    10225842
  • 财政年份:
    2021
  • 资助金额:
    $ 25.4万
  • 项目类别:

相似海外基金

Japanese Ethnogenesis: Oka Masao's Theory of Cultural Strata as a Hybrid Outcome of Scholarly Exchange between Austria and Japan
日本民族发生:冈正男的文化阶层理论是奥地利和日本之间学术交流的混合结果
  • 批准号:
    23K12262
  • 财政年份:
    2023
  • 资助金额:
    $ 25.4万
  • 项目类别:
    Grant-in-Aid for Early-Career Scientists
De-)constructing cultural colonialisms: A narratological investigation of Austria-Hungary's inner and extra-European discourses of identity and differ
解构文化殖民主义:对奥匈帝国内部和外部欧洲身份和差异话语的叙事学调查
  • 批准号:
    2877091
  • 财政年份:
    2023
  • 资助金额:
    $ 25.4万
  • 项目类别:
    Studentship
The Research about the Non University Higher Education in Austria
奥地利非大学高等教育研究
  • 批准号:
    22K02686
  • 财政年份:
    2022
  • 资助金额:
    $ 25.4万
  • 项目类别:
    Grant-in-Aid for Scientific Research (C)
International Cooperative Research on Lesson Study-based Teacher Education between Japan, Germany, and Austria
日本、德国、奥地利课本式教师教育国际合作研究
  • 批准号:
    22KK0032
  • 财政年份:
    2022
  • 资助金额:
    $ 25.4万
  • 项目类别:
    Fund for the Promotion of Joint International Research (Fostering Joint International Research (B))
IRES Track I: Exploring the Ecophysiology of Energy Balance in Vienna, Austria
IRES 第一轨:探索奥地利维也纳能量平衡的生态生理学
  • 批准号:
    1951995
  • 财政年份:
    2022
  • 资助金额:
    $ 25.4万
  • 项目类别:
    Standard Grant
How does the victimhood identity of right-wing populist parties in France, Germany, and Austria contribute to the rise in anti-Semitic hate crime?
法国、德国和奥地利右翼民粹主义政党的受害者身份如何导致反犹太仇恨犯罪的增加?
  • 批准号:
    2584860
  • 财政年份:
    2021
  • 资助金额:
    $ 25.4万
  • 项目类别:
    Studentship
IRES Track II: Complexity advanced studies institute - Germany, Austria, Italy, Netherlands (Complexity-GAINs)
IRES Track II:复杂性高级研究机构 - 德国、奥地利、意大利、荷兰 (Complexity-GAINs)
  • 批准号:
    2106013
  • 财政年份:
    2021
  • 资助金额:
    $ 25.4万
  • 项目类别:
    Standard Grant
Europe's Last Peasant War: Violence and Revolution in Austria-Hungary and its Successors, 1917-1945
欧洲最后的农民战争:奥匈帝国及其继承者的暴力与革命,1917-1945 年
  • 批准号:
    AH/V004093/1
  • 财政年份:
    2021
  • 资助金额:
    $ 25.4万
  • 项目类别:
    Research Grant
Implementation of incentive systems and nudges to promote environmentally conscious behavior ​and demonstration experiments in both Japan and Austria
实施激励制度和推动以促进环保意识行为
  • 批准号:
    21KK0027
  • 财政年份:
    2021
  • 资助金额:
    $ 25.4万
  • 项目类别:
    Fund for the Promotion of Joint International Research (Fostering Joint International Research (B))
IRES Track 1: Neurobiology and evolution of frog dance displays in Austria and India
IRES 轨道 1:奥地利和印度青蛙舞蹈表演的神经生物学和进化
  • 批准号:
    1952542
  • 财政年份:
    2020
  • 资助金额:
    $ 25.4万
  • 项目类别:
    Standard Grant
{{ showInfoDetail.title }}

作者:{{ showInfoDetail.author }}

知道了