Regulation of Rab activation at the Golgi complex

高尔基复合体 Rab 激活的调节

基本信息

  • 批准号:
    9197321
  • 负责人:
  • 金额:
    $ 29.02万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2016
  • 资助国家:
    美国
  • 起止时间:
    2016-06-01 至 2020-05-31
  • 项目状态:
    已结题

项目摘要

 DESCRIPTION (provided by applicant): The Golgi complex is the central sorting station for nearly a third of all proteins in eukaryotic cells, but how cells regulate the flow of material through this organelle remains unknown. Protein and membrane traffic into and out of the Golgi is controlled by Rab GTPases that function by recruiting effectors to generate, transport, and tether transport vesicles. The master regulators of these essential Rab pathways are the Rab-GEF proteins that must "decide" whether to activate their substrate Rabs. The TRAPP complexes are GEFs that activate Rabs at the Golgi, but it is unknown how the timing and magnitude of TRAPP complex activity is regulated. In the budding yeast model, there are two essential Rabs that control Golgi traffic: Ypt1 (Rab1), and Ypt31/32 (Rab11). The TRAPPI complex is the established activator of Ypt1 at early Golgi compartments. The GEF for Ypt31/32 is unknown, and is the subject of controversy. The TRAPPII complex has been proposed to serve as the GEF for Ypt31/32, although firm evidence for this hypothesis is lacking. The uncertainty surrounding the GEF for this critical trafficking pathway is hindering progress in the field. Using a biochemical approach, we have now obtained data that will resolve this controversy. By purifying the TRAPPII complex and performing physiological Rab activation assays, we have discovered that TRAPPII functions as a bone fide GEF for both Ypt1 and Ypt31/32. Importantly, robust GEF activity for Ypt31/32 is strictly dependent upon the presence of membranes, thus explaining why it was not observed previously by other groups, and implying the existence of an autoinhibitory mechanism. Our long-term goal is to uncover mechanisms governing the regulation of Golgi function. The goal of this project is to determine the mechanisms regulating the activation of Ypt1 and Ypt31/32 by the TRAPP complexes. In order to achieve our research goals, we propose the following three aims: 1) Dissect the mechanistic basis for TRAPPII activation of two different Rab GTPases. In vitro assays will be used to investigate how TRAPPII can activate two different substrates, and to ask why membranes are required for activation of Ypt31/32 but not Ypt1. We will then use yeast genetics and cell biology to characterize the functional consequences of perturbing TRAPPII activity in vivo, in order to understand how the TRAPPII complex is regulated in the context of Golgi trafficking. 2) Determine the mechanism and functional significance of TRAPPIII function at the Golgi. Emerging evidence points to TRAPPIII as the physiological GEF for Ypt1 at the early Golgi. We will investigate how TRAPPIII GEF activity is regulated and what role it plays in the cell. 3) Characterize the dynamics of TRAPPII and TRAPIII association with the Golgi. We will determine whether known interacting partners directly regulate the activity and dynamics of TRAPP complexes. We will also determine whether the TRAPP complexes are regulated by crosstalk with other Golgi-localized GTPases. In sum, these studies will lead to a comprehensive model for the regulation of the essential Golgi Rab trafficking pathways.


项目成果

期刊论文数量(0)
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科研奖励数量(0)
会议论文数量(0)
专利数量(0)

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J Christopher Fromme其他文献

J Christopher Fromme的其他文献

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{{ truncateString('J Christopher Fromme', 18)}}的其他基金

GTPase Regulation of the Golgi Complex
高尔基复合体的 GTP 酶调节
  • 批准号:
    10597649
  • 财政年份:
    2020
  • 资助金额:
    $ 29.02万
  • 项目类别:
GTPase Regulation of the Golgi Complex (Diversity Supplement 2023)
高尔基复合体的 GTPase 调节(多样性补充资料 2023)
  • 批准号:
    10800329
  • 财政年份:
    2020
  • 资助金额:
    $ 29.02万
  • 项目类别:
GTPase Regulation of the Golgi Complex
高尔基复合体的 GTP 酶调节
  • 批准号:
    10379948
  • 财政年份:
    2020
  • 资助金额:
    $ 29.02万
  • 项目类别:
Regulation of Rab activation at the Golgi complex
高尔基复合体 Rab 激活的调节
  • 批准号:
    9005350
  • 财政年份:
    2016
  • 资助金额:
    $ 29.02万
  • 项目类别:
Regulation of Arf GTPase activation at the Golgi complex
高尔基复合体 Arf GTP 酶激活的调节
  • 批准号:
    9234934
  • 财政年份:
    2012
  • 资助金额:
    $ 29.02万
  • 项目类别:
Regulation of Arf GTPase activation at the trans-Golgi network
跨高尔基体网络 Arf GTPase 激活的调节
  • 批准号:
    8245998
  • 财政年份:
    2012
  • 资助金额:
    $ 29.02万
  • 项目类别:
Regulation of Arf GTPase activation at the Golgi complex
高尔基复合体 Arf GTP 酶激活的调节
  • 批准号:
    9415454
  • 财政年份:
    2012
  • 资助金额:
    $ 29.02万
  • 项目类别:
Regulation of Arf GTPase activation at the trans-Golgi network
跨高尔基体网络 Arf GTPase 激活的调节
  • 批准号:
    8413049
  • 财政年份:
    2012
  • 资助金额:
    $ 29.02万
  • 项目类别:
Regulation of Arf GTPase activation at the trans-Golgi network
跨高尔基体网络 Arf GTPase 激活的调节
  • 批准号:
    9000156
  • 财政年份:
    2012
  • 资助金额:
    $ 29.02万
  • 项目类别:
EXOMER COMPLEX
外显子复合体
  • 批准号:
    8363377
  • 财政年份:
    2011
  • 资助金额:
    $ 29.02万
  • 项目类别:

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