Targeting of tail-anchored membrane proteins by the Get pathway.

通过 Get 途径靶向尾锚定膜蛋白。

基本信息

  • 批准号:
    8188012
  • 负责人:
  • 金额:
    $ 29.45万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2011
  • 资助国家:
    美国
  • 起止时间:
    2011-07-01 至 2016-06-30
  • 项目状态:
    已结题

项目摘要

DESCRIPTION (provided by applicant): The biogenesis of integral membrane proteins is an essential and complex process. Until recently, the targeted delivery of an important class, tail-anchored (TA) membrane proteins, was poorly understood. TA-proteins are defined topologically as containing a single trans-membrane domain (TM) near the C-terminus. This constraint prevents them from following the canonical signal recognition particle dependent co-translational targeting pathway. TA-proteins are involved in many key cellular processes including protein localization, vesicular trafficking, regulation of apoptosis and viral assembly and have been linked to a number of diseases. They are found in most eukaryotic membranes; however, they are initially delivered to either the endoplasmic reticulum (ER) or the mitochondrial outer membrane. TA-proteins are targeted to the ER by the newly discovered Get pathway (Guided entry of TA-proteins). In yeast, the central component of this pathway is the targeting factor Get3, a universally conserved ATPase that binds specifically to the TM of a TA-protein and uses ATP hydrolysis to deliver the TA-protein to the ER membrane. At the membrane, two proteins, Get1 and Get2, are thought to act as receptors for Get3 to ensure proper targeting and release of the TA-protein from Get3. Upstream of Get3, the proteins Get4, Get5 and Sgt2 are thought to mediate delivery to Get3 and may play a role in discriminating alternate delivery pathways. The identification of proteins in this pathway has provided an early framework for the targeting model. Recently, key structural work by our group, along with efforts by others, has begun to shed light on this process. Our early work has primed us to fully elucidate the roles of each component in the system. In the following proposal we describe how we plan to characterize each step in targeting both structurally and biochemically. The aims are to 1) determine the role of conformational changes and nucleotide hydrolysis in TA-protein targeting by Get3, 2) understand the process of discriminating TA- substrates and their delivery to Get3 and 3) elucidate the route of insertion of a TA-protein into a membrane. PUBLIC HEALTH RELEVANCE: Tail-anchor (TA) proteins, linked to a number of diseases such as cancer, are a diverse class of integral membrane proteins with key roles in many cellular processes. The broad importance of these proteins makes it critical that there is a detailed understanding of their biogenesis. The program proposed here aims to elucidate the mechanistic details of the biological principles that govern the synthesis of TA-proteins potentially leading to novel therapeutic strategies. !
描述(申请人提供):完整膜蛋白的生物发生是一个基本而复杂的过程。直到最近,对一类重要的膜蛋白--尾锚定(TA)膜蛋白的靶向递送还知之甚少。TA-蛋白在拓扑学上被定义为在C末端附近含有一个跨膜结构域(TM)。这一限制阻止了它们遵循典型的信号识别粒子依赖的共翻译靶向途径。TA蛋白参与了许多关键的细胞过程,包括蛋白定位、囊泡运输、细胞凋亡调控和病毒组装,并与许多疾病有关。它们存在于大多数真核细胞膜中;然而,它们最初被输送到内质网(ER)或线粒体外膜。TA蛋白通过新发现的GET途径(TA蛋白的引导进入)靶向内质网。在酵母中,这一途径的中心成分是靶向因子Get3,这是一种普遍保守的ATPase,它特异性地与TA蛋白的TM结合,并通过ATP水解将TA蛋白运送到内质网膜上。在膜上,两种蛋白质Get1和get2被认为是Get3的受体,以确保正确的靶向和从Get3释放TA-蛋白。在Get3的上游,Get4、Get5和SGT2蛋白被认为是介导Get3的传递,并可能在区分替代传递途径中发挥作用。该途径中蛋白质的鉴定为靶向模型提供了一个早期的框架。最近,我们小组的关键结构工作以及其他方面的努力已开始揭示这一进程。我们的早期工作为我们充分阐明系统中每个组件的作用做好了准备。在下面的提案中,我们描述了我们计划如何从结构和生化两个方面描述靶向的每一步。其目的是1)确定构象变化和核苷酸水解在Get3靶向TA蛋白中的作用;2)了解TA底物的识别过程并将它们传递给Get3;3)阐明TA蛋白插入膜的途径。 公共卫生相关性:尾锚(TA)蛋白与多种疾病(如癌症)有关,是一类在许多细胞过程中起关键作用的不同类别的完整膜蛋白。这些蛋白质的广泛重要性使得对它们的生物发生有一个详细的了解是至关重要的。该计划旨在阐明控制TA蛋白合成的生物学原理的机械细节,这些原理可能导致新的治疗策略。好了!

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 }}

William M. Clemons其他文献

William M. Clemons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('William M. Clemons', 18)}}的其他基金

A New Pradigm for the Rational Expression of Integral Membrane Proteins
整合膜蛋白合理表达的新范式
  • 批准号:
    9751901
  • 财政年份:
    2017
  • 资助金额:
    $ 29.45万
  • 项目类别:
Mechanistic details of key integral-membrane enzymes for antimicrobial discovery
用于抗菌发现的关键整合膜酶的机制细节
  • 批准号:
    9324275
  • 财政年份:
    2016
  • 资助金额:
    $ 29.45万
  • 项目类别:
Mechanistic details of key integral-membrane enzymes for antimicrobial discovery
用于抗菌发现的关键整合膜酶的机制细节
  • 批准号:
    9030128
  • 财政年份:
    2016
  • 资助金额:
    $ 29.45万
  • 项目类别:
Mechanistic details of key integral membrane enzymes for antimicrobial discovery
用于抗菌发现的关键整合膜酶的机制细节
  • 批准号:
    10158048
  • 财政年份:
    2016
  • 资助金额:
    $ 29.45万
  • 项目类别:
Mechanistic details of key integral-membrane enzymes for antimicrobial discovery
用于抗菌发现的关键整合膜酶的机制细节
  • 批准号:
    9751879
  • 财政年份:
    2016
  • 资助金额:
    $ 29.45万
  • 项目类别:
Mechanistic details of key integral membrane enzymes for antimicrobial discovery
用于抗菌发现的关键整合膜酶的机制细节
  • 批准号:
    10653003
  • 财政年份:
    2016
  • 资助金额:
    $ 29.45万
  • 项目类别:
Mechanistic details of key integral membrane enzymes for antimicrobial discovery
用于抗菌发现的关键整合膜酶的机制细节
  • 批准号:
    10436963
  • 财政年份:
    2016
  • 资助金额:
    $ 29.45万
  • 项目类别:
NIH Pioneer Award
美国国立卫生研究院先锋奖
  • 批准号:
    8144160
  • 财政年份:
    2011
  • 资助金额:
    $ 29.45万
  • 项目类别:
CLEMONS 12-2 PRT
克莱蒙斯 12-2 PRT
  • 批准号:
    8362340
  • 财政年份:
    2011
  • 资助金额:
    $ 29.45万
  • 项目类别:
Targeting of tail-anchored membrane proteins by the Get pathway.
通过 Get 途径靶向尾锚定膜蛋白。
  • 批准号:
    8689104
  • 财政年份:
    2011
  • 资助金额:
    $ 29.45万
  • 项目类别:
{{ showInfoDetail.title }}

作者:{{ showInfoDetail.author }}

知道了