Fine tuning the catalytic cycle of kinesin motors

微调驱动蛋白马达的催化循环

基本信息

  • 批准号:
    8083250
  • 负责人:
  • 金额:
    $ 30.02万
  • 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:
    2011-04-01 至 2015-03-31
  • 项目状态:
    已结题

项目摘要

DESCRIPTION (provided by applicant): Hedgehog (Hh) signaling is fundamental to many developmental processes in organisms as divergent as Drosophila melanogaster and humans. The Hh family of secreted proteins activates intracellular signaling cascades for a variety of cellular processes and plays an essential role in embryonic patterning and cell type specification. Vertebrate homologues of Hh are involved in patterning of limbs, lungs, hair follicles and other processes and misregulation of or mutations in Hh signaling genes lead to a number of developmental defects and disorders. Critical to Hh activation is a large protein complex termed the Hedgehog Signaling Complex (HSC). The HSC interprets the level of Hh activation by regulating the levels and activity of one of its components, the transcription factor Ci. Two other components of the HSC are the Ser/Thr protein kinase Fused (Fu) and the putative motor/scaffolding protein Costal-2 (Cos2). Cos2 has significant sequence identity to kinesin family motors, suggesting that Cos2 motility might be important for its function. It also appears to be enriched on microtubules in a manner that is attenuated when cells are exposed to Hh, again consistent with it being an Hh regulated kinesin family member. However, the lack of a key conserved catalytic sequence in Cos2 raises doubts as to whether it is a functional kinesin motor and it has been proposed that Cos2 functions solely as a scaffolding protein, binding and enriching various other Hh pathway components. In order to clarify the role Cos2 plays in Hh signaling, we will perform a detailed mechanistic analysis of its activity. Our preliminary results show that the Cos2 motor domain has both ATPase and GTPase activities. The proposed studies will explore in detail the Cos2 catalytic cycle, as well as characterizing the Cos2 protein interactome using structural and mechanistic approaches to investigate the interaction of Cos2 with microtubules and other binding partners. As a step towards achieving these goals, we have developed a bacterial-based system for the high level expression of a eukaryotic-like nonpolymerizing tubulin dimer. The high-resolution crystal structures to be obtained here will provide key insight into the mode of action of Cos2 in Hh signaling and may lead to novel therapeutic targets for regulation of Hedgehog signaling. PUBLIC HEALTH RELEVANCE: The Hedgehog (Hh) family of secreted proteins activates intracellular signaling cascades for a variety of cellular processes, plays an essential role in development, and disruption of the Hh pathway leads to an increasingly large number of different human pathologies. Costal-2 (Cos2) is a distant relative of cellular motor proteins, and is essential for proper signaling in the Hh pathway. This proposal seeks to characterize Cos2 in order to figure out exactly how it operates, a critical first step in designing rational preventative and curative strategies against diseases related to malfunctions in the Hh signaling pathway.
描述(由申请人提供):Hedgehog(Hh)信号传导是生物体(如黑腹果蝇和人类)许多发育过程的基础。分泌蛋白的Hh家族激活细胞内信号级联反应,用于各种细胞过程,并在胚胎模式和细胞类型特化中起重要作用。Hh的脊椎动物同源物参与四肢、肺、毛囊和其他过程的模式化,并且Hh信号传导基因的失调或突变导致许多发育缺陷和障碍。Hh激活的关键是一个大的蛋白质复合物,称为刺猬信号复合物(HSC)。HSC通过调节其组分之一转录因子Ci的水平和活性来解释Hh活化的水平。HSC的另外两种组分是Ser/Thr蛋白激酶融合(Fu)和推定的马达/支架蛋白Costal-2(Cos 2)。Cos 2与驱动蛋白家族马达具有显著的序列同一性,表明Cos 2运动性对其功能可能很重要。它也似乎是丰富的微管的方式,是衰减时,细胞暴露于Hh,再次与它是一个Hh调节驱动蛋白家族成员一致。然而,缺乏一个关键的保守的催化序列中的Cos 2提出了怀疑,它是否是一个功能性的驱动蛋白电机,它已被提出,Cos 2功能仅作为一个支架蛋白,结合和丰富各种其他Hh途径的组件。 为了阐明Cos 2在Hh信号传导中的作用,我们将对其活性进行详细的机制分析。我们的初步结果表明,Cos 2运动域具有ATP酶和GT3酶活性。拟议的研究将详细探讨Cos 2催化循环,以及表征Cos 2蛋白质相互作用组使用结构和机制的方法来研究Cos 2与微管和其他结合伙伴的相互作用。作为实现这些目标的一步,我们已经开发了一个基于细菌的系统,用于高水平表达真核生物样非聚合微管蛋白二聚体。这里获得的高分辨率晶体结构将为Hh信号传导中Cos 2的作用模式提供关键见解,并可能导致Hedgehog信号传导调节的新治疗靶点。 公共卫生相关性:Hedgehog(Hh)家族的分泌蛋白激活细胞内信号级联以用于多种细胞过程,在发育中起重要作用,并且Hh通路的破坏导致越来越多的不同人类病理。Costal-2(Cos 2)是细胞运动蛋白的远亲,并且对于Hh途径中的适当信号传导是必需的。该提案旨在描述Cos 2的特征,以便准确地了解它是如何运作的,这是设计合理的预防和治疗策略以对抗与Hh信号通路故障相关的疾病的关键第一步。

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 }}

Fredrick Jon Kull其他文献

Fredrick Jon Kull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('Fredrick Jon Kull', 18)}}的其他基金

Virulence gene regulators of enteric bacterial pathogens: Determining the structural and functional mechanisms of small molecule and polypeptide inhibitors
肠道细菌病原体的毒力基因调节因子:确定小分子和多肽抑制剂的结构和功能机制
  • 批准号:
    10586700
  • 财政年份:
    2022
  • 资助金额:
    $ 30.02万
  • 项目类别:
Control of virulence in Vibrio cholerae by fatty acids
通过脂肪酸控制霍乱弧菌的毒力
  • 批准号:
    9174511
  • 财政年份:
    2016
  • 资助金额:
    $ 30.02万
  • 项目类别:
Fine tuning the catalytic cycle of kinesin motors
微调驱动蛋白马达的催化循环
  • 批准号:
    8446463
  • 财政年份:
    2011
  • 资助金额:
    $ 30.02万
  • 项目类别:
Fine tuning the catalytic cycle of kinesin motors
微调驱动蛋白马达的催化循环
  • 批准号:
    8640193
  • 财政年份:
    2011
  • 资助金额:
    $ 30.02万
  • 项目类别:
Fatty acid related regulation of enteric infectious disease
肠道传染病的脂肪酸相关调节
  • 批准号:
    8030148
  • 财政年份:
    2011
  • 资助金额:
    $ 30.02万
  • 项目类别:
Fatty acid related regulation of enteric infectious disease
肠道传染病的脂肪酸相关调节
  • 批准号:
    8339441
  • 财政年份:
    2011
  • 资助金额:
    $ 30.02万
  • 项目类别:
Fine tuning the catalytic cycle of kinesin motors
微调驱动蛋白马达的催化循环
  • 批准号:
    8245013
  • 财政年份:
    2011
  • 资助金额:
    $ 30.02万
  • 项目类别:
Structural Analysis of Vibrio cholerae Virulence Gene Regulatory Proteins
霍乱弧菌毒力基因调控蛋白的结构分析
  • 批准号:
    8293819
  • 财政年份:
    2006
  • 资助金额:
    $ 30.02万
  • 项目类别:
Structural Analysis of Vibrio cholerae Virulence Gene Regulatory Proteins
霍乱弧菌毒力基因调控蛋白的结构分析
  • 批准号:
    7189792
  • 财政年份:
    2006
  • 资助金额:
    $ 30.02万
  • 项目类别:
Structural Analysis of Vibrio cholerae Virulence Gene Regulatory Proteins
霍乱弧菌毒力基因调控蛋白的结构分析
  • 批准号:
    7737871
  • 财政年份:
    2006
  • 资助金额:
    $ 30.02万
  • 项目类别:

相似海外基金

Double Incorporation of Non-Canonical Amino Acids in an Animal and its Application for Precise and Independent Optical Control of Two Target Genes
动物体内非规范氨基酸的双重掺入及其在两个靶基因精确独立光学控制中的应用
  • 批准号:
    BB/Y006380/1
  • 财政年份:
    2024
  • 资助金额:
    $ 30.02万
  • 项目类别:
    Research Grant
Quantifying L-amino acids in Ryugu to constrain the source of L-amino acids in life on Earth
量化 Ryugu 中的 L-氨基酸以限制地球生命中 L-氨基酸的来源
  • 批准号:
    24K17112
  • 财政年份:
    2024
  • 资助金额:
    $ 30.02万
  • 项目类别:
    Grant-in-Aid for Early-Career Scientists
Molecular recognition and enantioselective reaction of amino acids
氨基酸的分子识别和对映选择性反应
  • 批准号:
    23K04668
  • 财政年份:
    2023
  • 资助金额:
    $ 30.02万
  • 项目类别:
    Grant-in-Aid for Scientific Research (C)
Basic research toward therapeutic strategies for stress-induced chronic pain with non-natural amino acids
非天然氨基酸治疗应激性慢性疼痛策略的基础研究
  • 批准号:
    23K06918
  • 财政年份:
    2023
  • 资助金额:
    $ 30.02万
  • 项目类别:
    Grant-in-Aid for Scientific Research (C)
Molecular mechanisms how arrestins that modulate localization of glucose transporters are phosphorylated in response to amino acids
调节葡萄糖转运蛋白定位的抑制蛋白如何响应氨基酸而被磷酸化的分子机制
  • 批准号:
    23K05758
  • 财政年份:
    2023
  • 资助金额:
    $ 30.02万
  • 项目类别:
    Grant-in-Aid for Scientific Research (C)
Design and Synthesis of Fluorescent Amino Acids: Novel Tools for Biological Imaging
荧光氨基酸的设计与合成:生物成像的新工具
  • 批准号:
    2888395
  • 财政年份:
    2023
  • 资助金额:
    $ 30.02万
  • 项目类别:
    Studentship
Collaborative Research: RUI: Elucidating Design Rules for non-NRPS Incorporation of Amino Acids on Polyketide Scaffolds
合作研究:RUI:阐明聚酮化合物支架上非 NRPS 氨基酸掺入的设计规则
  • 批准号:
    2300890
  • 财政年份:
    2023
  • 资助金额:
    $ 30.02万
  • 项目类别:
    Continuing Grant
Structurally engineered N-acyl amino acids for the treatment of NASH
用于治疗 NASH 的结构工程 N-酰基氨基酸
  • 批准号:
    10761044
  • 财政年份:
    2023
  • 资助金额:
    $ 30.02万
  • 项目类别:
Lifestyle, branched-chain amino acids, and cardiovascular risk factors: a randomized trial
生活方式、支链氨基酸和心血管危险因素:一项随机试验
  • 批准号:
    10728925
  • 财政年份:
    2023
  • 资助金额:
    $ 30.02万
  • 项目类别:
Single-molecule protein sequencing by barcoding of N-terminal amino acids
通过 N 端氨基酸条形码进行单分子蛋白质测序
  • 批准号:
    10757309
  • 财政年份:
    2023
  • 资助金额:
    $ 30.02万
  • 项目类别:
{{ showInfoDetail.title }}

作者:{{ showInfoDetail.author }}

知道了