Collagen VI, a protein that forms microscopic beads-on-a-string fibres, holds nearly every human tissue together—from muscles and skin to blood vessels and kidneys—yet no one knows exactly how it assembles. Mutations in collagen VI cause muscular dystrophy, while too little of it is linked to osteoarthritis and too much drives fibrosis and tumour growth. Despite its importance, the protein’s size and complexity have kept its assembly mechanism a mystery. The researchers have already captured the first high-resolution image of any extracellular matrix fibre using cryo-electron microscopy, revealing key regions that likely control assembly. Now they will use a mini-collagen system to watch how three different collagen VI chains select partners and form the basic building block, then track how four of those blocks assemble into a microfibril. They will test their findings in living cells by tagging collagen VI and introducing targeted mutations to disrupt specific steps. This is fundamental science—understanding the rules of life at the molecular level. If successful, it could eventually guide tissue engineering strategies or help pharmaceutical companies design drugs that either boost or block collagen VI deposition in diseases where its levels go wrong.
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Collagen VI forms microfibrils that are important for providing mammalian tissues with their structure and mechanical strength by connecting cells with the surrounding extracellular matrix. Collagen VI is found in almost all tissues in the human body, for example the musculoskeletal system, skin, joints, lungs, eyes, kidneys and blood vessels. Unlike many other types of collagen, collagen VI does not have a typical fibrillar structure and organisation, instead it contains many globular domains and a short collagenous region, and forms microfibrils with a beads-on-a-string appearance. The importance of collagen VI in maintaining normal tissue function, is highlighted by mutations in collagen VI leading to muscular dystrophy and increased risk of cardiovascular disease. Moreover, a lack of collagen VI has been linked to osteoarthritis, and excessive collagen VI promotes fibrosis, inflammation and tumour growth. Although collagen VI is essential for maintaining normal tissue structure, its size and complexity have limited our understanding of its structure and the molecular details of how it assembles into microfibrils. The microfibril is assembled from three different collagen VI chains which form a heterotrimer, the basic building block of collagen VI, and four trimers come together to form the assembly unit of the microfibril. However, the molecular interactions that drive this assembly are not understood, which limits our understanding of collagen VI biology. Until recently, we had been unable to determine the structure of extracellular matrix fibrils due to their complexity, but advances in imaging are now enabling us to resolve these complex structures. Therefore, to support our proposal, we have recently determined the high-resolution structure of the bead region of the collagen VI microfibril using cryo-electron microscopy. This is the first high-resolution structure of any extracellular matrix fibrillar protein and our structure has revealed C-terminal regions that appear important for the formation of the microfibril. Therefore, in this project, we want to determine the molecular interactions that drive the different steps in collagen VI assembly. Using our mini-collagen VI expression system, we will use cryo-electron microscopy to image heterotrimers of different chain combinations and introduce mutations to test the requirements for chain selection and heterotrimerisation from different chains. Then we will determine the interactions underpinning the assembly of the collagen VI microfibril and image collagen VI microfibrils containing different chains. We will test our findings from these structures in cells, using endogenously tagged collagen VI to track assembly. Using this system, we will determine the consequences of disrupting specific interactions in collagen VI assembly, by introducing mutations designed to disrupt different assembly steps. As collagen VI microfibrils play a vital role in maintaining the normal structure of tissues, our research aligns with the “understanding the rules of life” BBSRC strategic priority. Understanding the molecular requirements for collagen VI microfibril assembly, which provide the mechanical properties of most mammalian tissues, could have significant health and economic benefits to the UK by providing valuable information towards novel tissue engineering strategies. Results from this study will not only be important for understanding collagen VI structure, but will also be of future interest to the pharmaceutical industry in developing therapeutics to modulate collagen VI deposition. As many human diseases are linked to excessive or insufficient collagen VI, our findings could provide new opportunities for future therapeutic intervention by selectively targeting collagen VI assembly or processing.
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