Evolution of protein intrinsic disorder

蛋白质内在紊乱的进化

• 批准号: RGPIN-2017-03907
• 负责人: Harrison, Paul
• 金额: $ 1.89万
• 依托单位: McGill University
• 依托单位国家: 加拿大
• 项目类别: Discovery Grants Program - Individual
• 财政年份: 2020
• 资助国家: 加拿大
• 起止时间: 2020-01-01 至 2021-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=709368
• 关键词: Evolution; protein; intrinsic; disorder

(This is a summary written simply, for the public to read, as per the NSERC instructions:-) Proteins are long molecules made of strings of small building blocks, called 'amino acids'. These amino acids have many different characters. Proteins do many different jobs in living organisms. They harvest energy, they transport and change chemicals, and form scaffolds for cells and tissues. Most proteins have a fixed shape or set of shapes that are designed for whatever job(s) they do. Some protein or protein parts, however, do not have a fixed shape, but instead they have a constantly changing shape, jiggling around like a string that never stays in one arrangement. These are called 'intrinsically disordered'. They use very different combinations of amino-acid building blocks to those that have a 'fixed shape'. As organisms evolve across many millions of years, the proteins in their cells and tissues also evolve and mutate, and take on new roles or modified old roles. By studying how this happens, we can figure out which parts of proteins are important for their jobs, and which are not. Also, examining how proteins evolve helps us to figure out whether the proteins are related to each other, or can do similar jobs. This process of studying the evolution of proteins is well understood for 'fixed-shape' proteins or protein parts. However, it is not well understood for the 'intrinsically disordered'. In this work, we are aiming to discover more about how intrinsically disordered proteins and protein parts evolve. In the right environments or contexts, some intrinsically disordered proteins can occasionally take on a fixed shape, that can be passed on to other copies of the same proteins. The proteins then all bundle together in protein assemblies called 'prions', that keep replicating the fixed shapes by passing them onto more and more of the intrinsically disordered proteins. The shapes of these prions are called 'amyloids'. These amyloids are long, twisted fibres that are also linked to a lot of human diseases of the brain and nervous system. We also study the evolution of these 'prion-forming' proteins and proteins that look like them. This work will advance our general knowledge of how proteins evolve, and how general mutation trends (that arise across all proteins in an organism) occur and affect individual protein evolution. This work will also help us to find and understand the important intrinsically disordered parts of proteins that are functional, and that are thus useful for biotechnology and, where they are linked to disease mechanisms, are potential targets for drug design. By understanding what parts of prion and prion-like proteins are functionally important and by analyzing how different parts of prion sequences evolve, we will be able to gain insights into the origins of similar proteins that are linked to human diseases. These advances will useful for humans in Canada and around the world.

(This是一个简单的总结，供公众阅读，按照NSERC的指示：-） 蛋白质是由称为“氨基酸”的小积木串组成的长分子。这些氨基酸具有许多不同的特性。蛋白质在生物体中做许多不同的工作。它们收集能量，运输和改变化学物质，形成细胞和组织的支架。大多数蛋白质都有一个固定的形状或一组形状，这些形状是为它们所做的任何工作而设计的。然而，一些蛋白质或蛋白质部分并没有固定的形状，而是不断变化的形状，像一根永远不会固定的绳子一样抖动。这些被称为“内在紊乱”。它们使用的氨基酸结构单元与那些具有“固定形状”的氨基酸结构单元非常不同。 随着生物体在数百万年的进化，其细胞和组织中的蛋白质也会进化和突变，并承担新的角色或修改旧的角色。通过研究这是如何发生的，我们可以弄清楚蛋白质的哪些部分对其工作很重要，哪些不重要。此外，研究蛋白质如何进化有助于我们弄清楚蛋白质是否彼此相关，或者可以做类似的工作。 这种研究蛋白质进化的过程对于“固定形状”蛋白质或蛋白质部分是很好理解的。然而，它并没有很好地理解为“内在无序”。在这项工作中，我们的目标是发现更多关于内在无序的蛋白质和蛋白质部分如何进化的信息。 在适当的环境或背景下，一些本质上无序的蛋白质偶尔会呈现出固定的形状，这种形状可以传递给相同蛋白质的其他副本。然后这些蛋白质都在蛋白质组装体中捆绑在一起，称为“朊病毒”，通过将它们传递到越来越多的内在无序的蛋白质上，不断复制固定的形状。这些朊病毒的形状被称为“淀粉样蛋白”。这些淀粉样蛋白是长而扭曲的纤维，也与许多人类大脑和神经系统疾病有关。我们还研究了这些“朊病毒形成”蛋白质和类似蛋白质的进化。 这项工作将推进我们对蛋白质如何进化的一般知识，以及一般突变趋势（在生物体中所有蛋白质中出现）如何发生并影响单个蛋白质进化。这项工作还将帮助我们发现和理解蛋白质中重要的内在无序部分，这些部分是功能性的，因此对生物技术很有用，并且在与疾病机制相关的地方，它们是药物设计的潜在目标。通过了解朊病毒和朊病毒样蛋白的哪些部分在功能上是重要的，并通过分析朊病毒序列的不同部分如何进化，我们将能够深入了解与人类疾病有关的类似蛋白质的起源。这些进步将对加拿大和世界各地的人类有用。