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.