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

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.

Collagen VI is a unique microfibrillar protein found in almost all mammalian tissues, such as the musculoskeletal system, skin and cornea. Collagen VI microfibrils are at the interface of cells and their surrounding matrix where they are essential for influencing cellular behaviour and tissue homeostasis. Their importance is highlighted as mutations result in muscular dystrophy and other pathologies. The microfibrils form a network connecting cells and matrix, however, our lack of knowledge on how collagen VI mediates interactions with matrix proteins and the cell surface, limits our understanding of the molecular mechanisms underpinning its essential function. Until now, the scale and complexity of collagen VI has limited its structural analysis, but with recent advances in cryoEM imaging, major progress is now possible. Therefore, our overarching aims are to determine the 3D structure of these unique biopolymers at the resolution of individual domains in physiological hydrated state. The hierarchical assembly of microfibrils results in the formation of complex interaction sites due to the involvement of multiple molecular chains which has presented a challenge in defining collagen VI interactions. Using the structure, we want to establish which domains are involved in collagen VI assembly, and map the spatial locations of important functional regions and interaction sites on the microfibril structure. Binding assays will test how interaction sites formed by assembly of collagen VI, support interactions between cell surface receptors and the matrix. We will also determine differences in collagen VI microfibril structure that contain different chains found in specific tissue contexts, with the aim of understanding the mechanism of this specialisation. Given the key role played by collagen VI as a mediator of tissue homeostasis in most mammalian tissues, our findings could inform future strategies for regenerative medicine to recapitulate native tissue function.