A kinesin-1 motor protein folds over and jams its own moving parts, and researchers want to learn how to unjam it—or jam it on command. Cells rely on a network of microtubules—like railway tracks—to move components around. Kinesin-1 proteins act as the vehicles, walking along these tracks to deliver cargo. When they fold into a compact shape, they stop moving; this autoinhibition is how the cell controls transport. But exactly how other molecules trigger the unfolding and reactivation remains poorly understood. This project will map that allosteric control mechanism, then use small protein fragments called peptides to artificially switch kinesin-1 on or off. If successful, the work will produce new molecular tools to manipulate cellular transport with precision. That could help researchers study what goes wrong in neurodegenerative diseases such as ALS and Alzheimer’s, where transport is disrupted, or in infections like HIV-1 and Salmonella, which hijack the same machinery. The project is fundamentally curiosity-driven—it asks how a molecular machine is controlled—but the design principles it uncovers could eventually be applied to other kinesins and the diseases they are linked to.
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This proposal brings together molecular cell biology and protein design to understand, manipulate and target a fundamental mechanism that controls how cells are organised. Cells possess many specialised components that must be in the right place at the right time to fulfil their functions. After their use, these components must be transported away for recycling or degradation. In addition, cells must adapt their organisation to meet functional demands or respond to changes in their environment. Mis-regulation or disruption of transport processes can contribute to human neurodegenerative conditions such as amyotrophic lateral sclerosis (ALS) and Alzheimer's Disease. In addition, cellular transport machinery can be 'hijacked' during viral (HIV-1) or bacterial (Salmonella) infections. Therefore, interrogating these transport systems is key to understanding the natural workings of cells, diseases, and infections. To move components around, cells use a transport system composed of a network of dynamic cables known as microtubules. Much like a railway network, these cables link together regions of the cell. Cells also possess 'vehicles' that travel along this network known as motor proteins. One of the most important is a family of protein complexes known as kinesin-1, which are the subject of this proposed study. Motor proteins can selectively attach to specific components inside cells and move them by walking along the microtubule network. Despite the importance of motor proteins across many areas of cell biology, we lack a proper understanding of how these complex machines are controlled. This proposal is all about understanding and exploiting this control within cells. Control is achieved by changes in the shape of the kinesin protein complex: it folds over allowing one part of the protein to reach around and jam the mechanism that allows the vehicles to move - this is known as autoinhibition. Our recent BBSRC-funded work (BB/W005581/1) has established some new key principles for how this works. The next step is to understand how the complex is unjammed and activated at the right place and time. We propose that this process is allosteric - where the activity of kinesin-1 is controlled by means of a conformational change induced by a different molecule(s). This proposal focuses on understanding that molecular mechanism. Our recent work also demonstrates new opportunities to design molecules that may enable intervention in transport processes. In this proposal, we ask: can we make the motor do more work, less work, or direct its activity to specific jobs? Eventually, we want to explore if and how these ideas transpose to kinesins and the diseases they are implicated in. To do this, we will develop the capacity to acutely and specifically control kinesin activity using small fragments of proteins called peptides. If successful, the impacts would extend well beyond the kinesin-1 field because the mechanisms we seek to target are ubiquitous throughout cell biology. Together, this research addresses cutting-edge fundamental cellular dynamics and sits squarely within the frontier bioscience and understanding the rules of life remit of the BBSRC. Moreover, aligned with the UK National Vision for Engineering Biology, by employing protein design, it applies insights from complex natural systems to develop a quantitative understanding and new biological tools for engineering-biology and biomedical applications.
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