Why do proteins aggregate under flow?

为什么蛋白质在流动下会聚集？

• 批准号: 2271297
• 金额: --
• 依托单位: University of Leeds
• 依托单位国家: 英国
• 项目类别: Studentship
• 财政年份: 2019
• 资助国家: 英国
• 起止时间: 2019 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=studentship-2271297
• 关键词: Why; do; proteins; aggregate; under

The function and stability of proteins are intimately linked to their environment and consequently, changes in environmental factors such as pH can trigger conformational changes that in turn modulate protein function. Forces exerted onto proteins during fluid flow (i.e.hydrodynamic forces) are also used in Nature controlling processes such as blood clotting and spider silk formation but our understanding of this process is limited. To address this question, we have developed an instrument to that mimics these forces and used it to show that that fluid flow can drive the aggregation of a small test protein (BSA) by triggering unfolding, exposing new protein surfaces with greater self-affinity, leading to aggregation (see Dobson et al. (2017) Proc Natl Acad Sci USA. 114:4673-4678). In addition to in vivo processes, fluid-flow induced unfolding and aggregation presents a huge obstacle to the large-scale manufacture of protein-based therapeutics and sometimes even prevents the translation of a promising candidate therapeutic to an effective and safe medicine. Protein-based medicines, known as biopharmaceuticals have emerged as powerful and versatile medicines with applications in auto-immune disease and cancer with antibody-based therapies having sales of $123 billion in 2017. The goal of this BBSRC Collaborative Training Partnership PhD studentship between the Astbury Centre for Structural and Molecular Biology and Medimmune, therefore, is to apply Leeds' unique expertise in protein (un)folding mechanisms, biophysical characterisation and hydrodynamic flow to identify the mechanism of flow-induced unfolding of test proteins and biopharmaceuticals provided by Medimmune. This fundamental study will ultimately facilitate the economic production of current and next generation high-value bio-pharmaceuticals.

蛋白质的功能和稳定性与其环境密切相关，因此，环境因素如pH的变化可以触发构象变化，进而调节蛋白质的功能。流体流动过程中施加在蛋白质上的力(即流体动力力)也用于自然界的控制过程，如血液凝结和蜘蛛丝的形成，但我们对这一过程的了解有限。为了解决这个问题，我们开发了一种仪器来模拟这些力，并用它来证明流体流动可以通过触发展开来驱动小测试蛋白(BSA)的聚集，从而暴露出具有更大自亲和力的新蛋白质表面，从而导致聚集(见Dobson等人。(2017)Proc Natl Acad Sci USA。114：4673-4678)。除了体内的过程外，流体诱导的展开和聚集对基于蛋白质的治疗药物的大规模生产构成了巨大的障碍，有时甚至阻碍了有前途的候选治疗药物向有效和安全的药物的转化。以蛋白质为基础的药物，即生物制药，已经成为功能强大、用途广泛的药物，应用于自身免疫性疾病和癌症，基于抗体的疗法在2017年的销售额达到1230亿美元。因此，Astbury结构和分子生物学中心与Medimmune之间的BBSRC协作培训伙伴关系博士研究生项目的目标是应用利兹在蛋白质(UN)折叠机制、生物物理特性和流体动力学方面的独特专业知识，以确定Medimmune提供的测试蛋白质和生物制药的流动诱导展开机制。这项基础性研究最终将促进当前和下一代高价值生物药物的经济生产。