Structure and Interactions at the Cell-Matrix Interface Mediated by Collagen VI

胶原VI形成微纤维，通过将细胞与其周围的细胞外基质连接，为我们的组织提供其结构和强度。VI型胶原蛋白几乎存在于人体的所有组织中，例如肌肉骨骼系统，我们的皮肤，关节，肺，眼睛，肾脏和血管。与许多其他类型的胶原蛋白不同，胶原蛋白VI不具有胶原蛋白的典型纤维状结构和组织，相反，它是独特的，因为它主要含有具有短胶原区域的球状蛋白结构域，并形成具有串珠外观的微纤维。胶原蛋白VI是重要的在维持我们的组织的正常功能在我们的整个生命过程。这一点被强调为VI型胶原蛋白的突变会导致肌肉萎缩症，而VI型胶原蛋白的缺乏与衰老相关的疾病有关，包括骨关节炎和骨质疏松症。胶原蛋白VI在细胞周围丰富，并结合细胞表面上的受体。它还与细胞外基质中发现的一系列不同蛋白质相互作用，形成将细胞连接到基质的网络。这种连接对于我们组织的正确功能、修复和维护是必要的，但是我们对VI型胶原蛋白结构的有限了解是理解其功能的主要障碍。此外，胶原VI必须组装成微纤维，以形成与不同蛋白质和细胞表面受体结合所需的正确相互作用位点。这阻碍了以前的分析，以确定基质蛋白和细胞表面受体的结合位置。到目前为止，由于细胞外基质微纤维的复杂性，我们还不能将其成像到高分辨率，但冷冻电子显微镜的最新进展现在使其成为可能。因此，我们工作的主要目的是使用冷冻电子显微镜来了解胶原VI微纤维的结构，我们相信这将向我们展示它们是如何组装的，并定位与其结合伙伴相互作用的重要位点。我们将确定在离散的组织特异性位置发现的含有不同组分链的VI型胶原微纤维之间发生了什么差异，以了解它们的组织特异性功能。最后，我们将发现胶原VI如何使用胶原VI的组装形式桥接基质蛋白和细胞表面受体，并了解它如何形成连接它们的网络。这将有助于了解VI型胶原微纤维如何随组织类型而变化，以及它们的结构如何支撑它们在组织组装和组织维护中的重要作用。了解这些支撑正常组织结构的分子要求可能对英国的健康和经济产生重大影响。胶原蛋白VI在维持经历年龄相关退化的组织的正常结构和功能方面起着至关重要的作用，例如皮肤，眼睛和肌肉骨骼系统。事实上，在骨质疏松的骨骼中发现了VI型胶原蛋白的减少，并与骨关节炎关节的加速退化有关，因此鉴于VI型胶原蛋白的基本功能和广泛分布，我们的研究结果可以为未来的治疗干预提供新的机会，有效的治疗将显着改善老年人口的生活质量。

Collagen VI forms microfibrils that are important for providing our tissues with their structure and strength by connecting cells with their surrounding extracellular matrix. Collagen VI is found in almost all tissues in the human body, for example the musculoskeletal system, our skin, joints, lungs, eyes, kidneys and blood vessels. Unlike many other types of collagens, collagen VI does not have the typical fibrillar structure and organisation of a collagen, rather it is unique in that it mainly contains globular protein domains with a short collagenous region, and forms microfibrils with a beads-on-a-string appearance. Collagen VI is important in maintaining the normal function of our tissues throughout our life course. This is highlighted as mutations in collagen VI lead to muscular dystrophy, and a lack of collagen VI has been linked to conditions related to ageing, including osteoarthritis and osteoporosis. Collagen VI Is abundant around cells and binds receptors on the cell surface. It also interacts with a range of different proteins found in the extracellular matrix forming a network that connects cells to the matrix. This connection is needed for the correct function, repair and maintenance of our tissues but our limited knowledge regarding the structure of collagen VI presents a major obstacle to understanding its function. Also, collagen VI must assemble into microfibrils to form the correct interaction sites needed for binding to different proteins and cell surface receptors. This has hampered previous analyses to define the binding locations for matrix proteins and cell surface receptors. Up until now, we have not been able to image extracellular matrix microfibrils to high resolution due to their complexity but recent advances in cryo-electron microscopy now make this possible. Therefore, the main aim of our work is to understand the structure of collagen VI microfibrils using cryo-electron microscopy, which we believe will show us how they are assembled and locate sites important for interacting with their binding partners. We will determine what differences occur between collagen VI microfibrils containing different component chains, found in discrete tissue-specific locations, to understand their tissue-specific function. Finally, we will discover how collagen VI bridges matrix proteins and cell surface receptors using the assembled forms of collagen VI and understand how it forms networks linking them. Together this will lead to an understanding of how collagen VI microfibrils change with tissue type and how their structure underpins their important roles in tissue assembly and tissue maintenance.Understanding these molecular requirements underpinning normal tissue structure could have significant health and economic benefits to the UK. Collagen VI plays a vital role in maintaining the normal structure and function of tissues that undergo age-related deterioration, such as the skin, eyes and musculoskeletal system. Indeed, a reduction in collagen VI is found in osteoporotic bones and linked to accelerated degeneration in osteoarthritic joints so given the essential function and wide-distribution of collagen VI, our findings could provide new opportunities for future therapeutic intervention and effective treatment would significantly improve the quality of life of an ageing population.