Protein folding and stability in the stress sensing machinery of stromal interaction molecules.
基质相互作用分子的应力传感机制中的蛋白质折叠和稳定性。
基本信息
- 批准号:RGPIN-2014-05239
- 负责人:
- 金额:$ 2.55万
- 依托单位:
- 依托单位国家:加拿大
- 项目类别:Discovery Grants Program - Individual
- 财政年份:2014
- 资助国家:加拿大
- 起止时间:2014-01-01 至 2015-12-31
- 项目状态:已结题
- 来源:
- 关键词:
项目摘要
All animal cells which have a discrete nucleus use calcium (Ca2+) to signal processes that are an integral part of their lifecycle, ranging from cell stress responses to cell division and suicide. These eukaryotic cells use a Ca2+ signaling toolkit comprised of protein molecules specifically tailored to the environment of the cell. Many components of the toolkit rely on vast differences in Ca2+ levels to mediate a specific cell signal. For example, stromal interaction molecules (STIMs) are located in a specialized cellular compartment, the endoplasmic reticulum (ER), containing high Ca2+ levels needed to process many of the protein machinery encoded in genomes; further, STIMs respond to the depletion of Ca2+ from the ER by changing shape and moving to near the periphery of the cell where interactions occur with another Ca2+ toolkit component, the Orai channel proteins. This interaction causes Orai channels located on the outer membrane to open, allowing Ca2+ to move from the high outside concentration to the low inside levels with minimal energy expenditure. The resultant elevation in intracellular Ca2+ is the signal which triggers the wide ranging cellular responses; further, this specific series of changes in compartmentalized Ca2+ levels is called store operated Ca2+ entry (SOCE) since it is dependent on ER stored Ca2+ levels. This research program aims to study how STIMs from relatively simple organisms such as the roundworm and the fruit fly sense changes in ER Ca2+ levels and how these mechanisms compare to more evolved organisms such as vertebrates. Additionally, the work proposes to investigate why higher order animals use two different STIM molecules to sense changes in ER Ca2+ levels, while lower organisms require only one. In order to answer these questions in a specific manner, we propose to express and isolate highly pure proteins corresponding to the STIM machinery responsible for ER Ca2+ sensing. Further, we plan to characterize the ability of the respective structural features to endure chemical and temperature stresses as well as a how Ca2+ levels alter the tolerances. Similarly, we aim to assess the effects that chemical modifications often occurring in ER proteins have on these structural characteristics and the role that species-specific regions of STIM closely apposed to the Ca2+ sensing machinery have on these features. We anticipate that the minimal Ca2+ sensing machinery within STIM molecules exhibit structural and interaction differences mediated by adaptive variations in the protein sequences; moreover, we believe that each STIM molecule employs the highly variable regions outside the minimal Ca2+ sensing machinery as well as natural chemical modifications to fine tune the structural responses to cellular stresses that include changes in Ca2+ levels, temperature and reactive oxygen species, in an organism- and STIM subtype-specific manner. This research program will provide insight into the features vital for dictating specific sensory functions of the Ca2+ signaling toolkit in lower compared to higher eukaryotes, information which is currently lacking in the broad Ca2+ signaling research field. Further, the work will provide new data on the roles that naturally occurring chemical modifications have on mediating the structural durability of STIMs, relatable to other ER-resident proteins. Importantly, this data will provide bases for the development of new research tools, engineered to sense changes in Ca2+, temperature and reactive oxygen species. Finally, the research will benefit Canada by providing multidisciplinary training for undergraduate, graduate and postdoctoral fellows that will develop a broad skill set for future careers in academia and/or industry.
所有具有离散细胞核的动物细胞都使用钙(Ca 2+)来发出信号,这些信号是其生命周期的一个组成部分,从细胞应激反应到细胞分裂和自杀。这些真核细胞使用由专门针对细胞环境定制的蛋白质分子组成的Ca 2+信号工具包。该工具包的许多组件依赖于Ca 2+水平的巨大差异来介导特定的细胞信号。例如,基质相互作用分子(stromal interaction molecules,STIM)位于专门的细胞区室,即内质网(endoplasmic reticulum,ER),其含有加工基因组中编码的许多蛋白质机器所需的高Ca 2+水平;此外,STIM通过改变形状并移动到细胞周边附近与另一种Ca 2+工具包组分发生相互作用,奥赖通道蛋白。这种相互作用导致位于外膜上的奥赖通道打开,允许Ca 2+以最小的能量消耗从高的外部浓度移动到低的内部水平。细胞内Ca 2+的升高是触发广泛的细胞反应的信号;此外,这一特定的一系列区室化Ca 2+水平的变化被称为钙库操纵的Ca 2+内流(SOCE),因为它依赖于ER储存的Ca 2+水平。该研究计划旨在研究来自相对简单的生物(例如蛔虫和果蝇)的STIM如何感知ER Ca 2+水平的变化,以及这些机制与脊椎动物等更进化的生物相比如何。此外,这项工作还提出了研究为什么高阶动物使用两种不同的STIM分子来感知ER Ca 2+水平的变化,而低等生物只需要一种。为了以特定的方式回答这些问题,我们建议表达和分离与负责ER Ca 2+传感的STIM机制相对应的高纯度蛋白质。此外,我们计划表征各自结构特征耐受化学和温度应力的能力,以及Ca 2+水平如何改变公差。同样,我们的目标是评估的影响,经常发生在ER蛋白的化学修饰对这些结构特征和作用,物种特异性区域的STIM紧密并列的Ca 2+传感器对这些功能。我们预期STIM分子内的最小Ca 2+感应机制表现出由蛋白质序列中的适应性变异介导的结构和相互作用差异;此外,我们相信每个STIM分子都利用最小Ca 2+感应机制之外的高度可变区域以及天然化学修饰来微调对细胞应激的结构响应,包括Ca 2+水平的变化,温度和活性氧物种,在生物体和STIM亚型特异性的方式。这项研究计划将提供深入了解的功能至关重要的指示特定的感觉功能的Ca 2+信号工具包在较低的高等真核生物相比,目前缺乏广泛的Ca 2+信号研究领域的信息。此外,这项工作将提供有关天然化学修饰在介导STIM结构耐久性方面的作用的新数据,与其他ER驻留蛋白相关。重要的是,这些数据将为开发新的研究工具提供基础,这些工具旨在感知Ca 2+,温度和活性氧的变化。最后,该研究将通过为本科生,研究生和博士后研究员提供多学科培训使加拿大受益,这些培训将为学术界和/或工业界的未来职业发展提供广泛的技能。
项目成果
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Stathopulos, Peter其他文献
STIM1 couples to ORAI1 via an intramolecular transition into an extended conformation.
- DOI:
10.1038/emboj.2011.79 - 发表时间:
2011-05-04 - 期刊:
- 影响因子:11.4
- 作者:
Muik, Martin;Fahrner, Marc;Schindl, Rainer;Stathopulos, Peter;Frischauf, Irene;Derler, Isabella;Plenk, Peter;Lackner, Barbara;Groschner, Klaus;Ikura, Mitsuhiko;Romanin, Christoph - 通讯作者:
Romanin, Christoph
Stathopulos, Peter的其他文献
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{{ truncateString('Stathopulos, Peter', 18)}}的其他基金
Molecular mechanisms regulating the form and function of atypical calcium sensor proteins.
调节非典型钙传感器蛋白的形式和功能的分子机制。
- 批准号:
RGPIN-2020-07171 - 财政年份:2022
- 资助金额:
$ 2.55万 - 项目类别:
Discovery Grants Program - Individual
Molecular mechanisms regulating the form and function of atypical calcium sensor proteins.
调节非典型钙传感器蛋白的形式和功能的分子机制。
- 批准号:
RGPIN-2020-07171 - 财政年份:2021
- 资助金额:
$ 2.55万 - 项目类别:
Discovery Grants Program - Individual
Molecular mechanisms regulating the form and function of atypical calcium sensor proteins.
调节非典型钙传感器蛋白的形式和功能的分子机制。
- 批准号:
RGPIN-2020-07171 - 财政年份:2020
- 资助金额:
$ 2.55万 - 项目类别:
Discovery Grants Program - Individual
Protein folding and stability in the stress sensing machinery of stromal interaction molecules.
基质相互作用分子的应力传感机制中的蛋白质折叠和稳定性。
- 批准号:
RGPIN-2014-05239 - 财政年份:2019
- 资助金额:
$ 2.55万 - 项目类别:
Discovery Grants Program - Individual
Microscale thermophoresis for assessing diverse molecular interactions.
用于评估不同分子相互作用的微尺度热泳。
- 批准号:
RTI-2020-00485 - 财政年份:2019
- 资助金额:
$ 2.55万 - 项目类别:
Research Tools and Instruments
Protein folding and stability in the stress sensing machinery of stromal interaction molecules.
基质相互作用分子的应力传感机制中的蛋白质折叠和稳定性。
- 批准号:
RGPIN-2014-05239 - 财政年份:2018
- 资助金额:
$ 2.55万 - 项目类别:
Discovery Grants Program - Individual
Protein folding and stability in the stress sensing machinery of stromal interaction molecules.
基质相互作用分子的应力传感机制中的蛋白质折叠和稳定性。
- 批准号:
RGPIN-2014-05239 - 财政年份:2017
- 资助金额:
$ 2.55万 - 项目类别:
Discovery Grants Program - Individual
Protein folding and stability in the stress sensing machinery of stromal interaction molecules.
基质相互作用分子的应力传感机制中的蛋白质折叠和稳定性。
- 批准号:
RGPIN-2014-05239 - 财政年份:2016
- 资助金额:
$ 2.55万 - 项目类别:
Discovery Grants Program - Individual
Protein folding and stability in the stress sensing machinery of stromal interaction molecules.
基质相互作用分子的应力传感机制中的蛋白质折叠和稳定性。
- 批准号:
RGPIN-2014-05239 - 财政年份:2015
- 资助金额:
$ 2.55万 - 项目类别:
Discovery Grants Program - Individual
Protein structure, dynamics, folding, misfolding and disease
蛋白质结构、动力学、折叠、错误折叠和疾病
- 批准号:
304990-2004 - 财政年份:2006
- 资助金额:
$ 2.55万 - 项目类别:
Postdoctoral Fellowships
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Protein folding and stability in the stress sensing machinery of stromal interaction molecules.
基质相互作用分子的应力传感机制中的蛋白质折叠和稳定性。
- 批准号:
RGPIN-2014-05239 - 财政年份:2019
- 资助金额:
$ 2.55万 - 项目类别:
Discovery Grants Program - Individual