Control and functionalization of protein nanofibrils using genetic and chemical modification to define assembly mechanisms and design principles

使用遗传和化学修饰来控制和功能化蛋白质纳米纤维,以定义组装机制和设计原则

基本信息

  • 批准号:
    RGPIN-2019-05229
  • 负责人:
  • 金额:
    $ 1.75万
  • 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:
    2021
  • 资助国家:
    加拿大
  • 起止时间:
    2021-01-01 至 2022-12-31
  • 项目状态:
    已结题

项目摘要

This research program seeks a better understanding of protein aggregation for applications in food quality, safety and human health. Protein amyloid fibrils, or `nanofibrils', are a highly organized type of protein aggregate associated with disease (e.g., Alzheimer's, ALS & mad cow) in certain cases, while in other cases they play a functional role (e.g., bacterial biofilm, barnacle adhesion, and human melanin synthesis). A mechanistic understanding of protein nanofibril formation could be used both to prevent unwanted aggregation (i.e., disease or bacterial biofilm formation) and to develop novel biomimetic materials and devices, such as catalytic arrays, biosensors, cell-scaffolds, bioelectronics, and controlled-release of bioactive compounds. These may find applications in food processing (enzyme immobilization for bioreactors and biosensors), tissue engineering (cultured meat for food; cultured tissues for medicine) or as functional foods (controlled release of bioactives). Protein nanofibrils have several unique properties, including a high aspect ratio (=1000:10 nm), strength, and stability, a unique surface chemistry, and the ability to self-propagate. A major challenge is that the design rules for building protein nanofibrils are not well known. Proteins can be induced to self-assemble into nanofibrils, threads of protein a few molecules in width and 1000's in length, in a complex process that follows different pathways, involving protein unfolding, misfolding, oligomer formation, proto-fibril and mature fibril formation. A second challenge is that utilization of protein nanofibrils for creating functional materials requires the ability to chemically modify proteins site-specifically, selectively, and in a manner compatible with the fibril structure. Targeting specific locations on a protein generally cannot rely on naturally abundant functional groups (e.g., amine, carboxylic acid and sulfhydryl groups), as these are present at multiple locations and their reactivity is limited to certain pH and redox conditions. To overcome these limitations, new protein engineering tools will be used to genetically insert `click' chemical groups into specific sites of model proteins to allow for chemical labelling in a well-defined, efficient manner. These click groups are inert to biological molecules and react only with a specific partner, which will be used to conjugate the nanofibrils with other functional molecules (e.g., peptides, enzymes, carbohydrates, lipids, DNA, nanoparticles, fluorescent dyes). Biophysical tools will be used to examine the effects of such genetic and chemical modifications on fibril assembly, structure and functionality. This platform will be used to examine the mechanism of fibril assembly and to create new nanoscale materials and devices (e.g., biosensors, ordered enzyme-arrays, & materials for controlled release) that ultimately may help enhance food quality and safety.
这项研究计划寻求更好地了解蛋白质聚集在食品质量、安全和人类健康方面的应用。蛋白质淀粉样原纤维,或‘纳米纤维’,是一种高度组织化的蛋白质聚集体,在某些情况下与疾病(例如阿尔茨海默病、肌萎缩侧索硬化症和疯牛病)有关,而在其他情况下则发挥功能作用(例如细菌生物膜、藤壶粘连和人类黑色素合成)。从机理上理解蛋白质纳米纤维的形成既可以用于防止不必要的聚集(即疾病或细菌生物膜的形成),也可以用于开发新型仿生材料和设备,如催化阵列、生物传感器、细胞支架、生物电子学和生物活性化合物的控制释放。它们可能在食品加工(生物反应器和生物传感器的酶固定化)、组织工程(用于食品的培养肉类;用于医药的培养组织)或作为功能食品(生物活性物质的受控释放)中得到应用。蛋白质纳米纤维具有几个独特的性质,包括高纵横比(=1000:10 nm)、强度和稳定性、独特的表面化学以及自我繁殖的能力。一个主要的挑战是,构建蛋白质纳米纤维的设计规则并不广为人知。蛋白质可以被诱导自组装成纳米纤维,几个分子宽的蛋白质线和1000‘S长的蛋白质线,在一个复杂的过程中遵循不同的途径,包括蛋白质去折叠、错折叠、低聚物形成、原纤维和成熟纤维的形成。第二个挑战是,利用蛋白质纳米纤维来创造功能材料,需要有能力对蛋白质进行化学修饰--特异性、选择性地,并以与纤维结构兼容的方式。针对蛋白质的特定位置通常不能依赖于自然丰富的官能团(例如,胺、羧酸和巯基),因为这些官能团存在于多个位置,其反应活性仅限于特定的pH和氧化还原条件。为了克服这些限制,将使用新的蛋白质工程工具在模型蛋白质的特定位置上以基因方式插入“点击”化学基团,以便以明确、有效的方式进行化学标记。这些点击基团对生物分子来说是惰性的,并且只与特定的伙伴反应,该伙伴将用于将纳米纤维与其他功能分子(例如,肽、酶、碳水化合物、脂类、DNA、纳米颗粒、荧光染料)结合。生物物理工具将被用来检查这种遗传和化学修饰对纤维组装、结构和功能的影响。该平台将被用来研究纤维组装的机制,并创造新的纳米材料和设备(例如,生物传感器、有序酶阵列和控制释放材料),最终可能有助于提高食品质量和安全。

项目成果

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Dee, Derek其他文献

Comparison of solution structures and stabilities of native, partially unfolded and partially refolded pepsin
  • DOI:
    10.1021/bi061270i
  • 发表时间:
    2006-11-28
  • 期刊:
  • 影响因子:
    2.9
  • 作者:
    Dee, Derek;Pencer, Jeremy;Yada, Rickey Y.
  • 通讯作者:
    Yada, Rickey Y.

Dee, Derek的其他文献

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{{ truncateString('Dee, Derek', 18)}}的其他基金

Control and functionalization of protein nanofibrils using genetic and chemical modification to define assembly mechanisms and design principles
使用遗传和化学修饰来控制和功能化蛋白质纳米纤维,以定义组装机制和设计原则
  • 批准号:
    RGPIN-2019-05229
  • 财政年份:
    2022
  • 资助金额:
    $ 1.75万
  • 项目类别:
    Discovery Grants Program - Individual
Control and functionalization of protein nanofibrils using genetic and chemical modification to define assembly mechanisms and design principles
使用遗传和化学修饰来控制和功能化蛋白质纳米纤维,以定义组装机制和设计原则
  • 批准号:
    RGPIN-2019-05229
  • 财政年份:
    2020
  • 资助金额:
    $ 1.75万
  • 项目类别:
    Discovery Grants Program - Individual
Control and functionalization of protein nanofibrils using genetic and chemical modification to define assembly mechanisms and design principles
使用遗传和化学修饰来控制和功能化蛋白质纳米纤维,以定义组装机制和设计原则
  • 批准号:
    DGECR-2019-00087
  • 财政年份:
    2019
  • 资助金额:
    $ 1.75万
  • 项目类别:
    Discovery Launch Supplement
Control and functionalization of protein nanofibrils using genetic and chemical modification to define assembly mechanisms and design principles
使用遗传和化学修饰来控制和功能化蛋白质纳米纤维,以定义组装机制和设计原则
  • 批准号:
    RGPIN-2019-05229
  • 财政年份:
    2019
  • 资助金额:
    $ 1.75万
  • 项目类别:
    Discovery Grants Program - Individual
Folding mechanism of an aspartic peptidase
天冬氨酸肽酶的折叠机制
  • 批准号:
    333415-2006
  • 财政年份:
    2008
  • 资助金额:
    $ 1.75万
  • 项目类别:
    Postgraduate Scholarships - Doctoral
Folding mechanism of an aspartic peptidase
天冬氨酸肽酶的折叠机制
  • 批准号:
    333415-2006
  • 财政年份:
    2007
  • 资助金额:
    $ 1.75万
  • 项目类别:
    Postgraduate Scholarships - Doctoral
Folding mechanism of an aspartic peptidase
天冬氨酸肽酶的折叠机制
  • 批准号:
    333415-2006
  • 财政年份:
    2006
  • 资助金额:
    $ 1.75万
  • 项目类别:
    Postgraduate Scholarships - Doctoral

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