Cargo recognition by kinesin-1 and its role in activation of transport

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Cells possess many specialised components that must be in the right place at the right time to fulfil their function. After their use, these components must be transported away for recycling or degradation. Mis-regulation or disruption of these transport processes can contribute to many human diseases ranging from neurodegenerative conditions such as Alzheimer's disease to cancer and even contribute to viral infections by HIV-1 or bacterial infections such as Salmonella. To move components around, cells use a transport system composed of a network of cables known as the microtubule network. Much like a railway network, these cables link together regions of the cell. Cells possess vehicles that travel along this network known as molecular motors, of which our proposed motor of study, kinesin-1, is one of the most important. These motors can selectively attach to cellular components and move them on the microtubule network. Despite their importance across so many areas of cell biology, we lack a proper understanding of how these motors recognise the cargo that they carry. The Dodding and Steiner groups at the Randall Division of Cell and Molecular Biophysics at King's College have collaborated to tackle this important problem and recently managed to take a big step forward. We have shown how kinesin-1 recognizes one of its cargoes known as SKIP - a cellular protein usurped by Salmonella for its kinesin-1 binding function. This breakthrough now gives us the exciting opportunity to study how kinesin-1 recognises is many other cargoes with diverse functions. We propose to do that here.We also know that cargoes themselves can control when motors attach to the transport network and move. In the absence of cargo, motors are inactive and don't move however when cargo are attached a switch occurs which allows motors to attach to the transport network and move. This is perhaps analogous to giving a taxi driver a signal to drive off when you are safely in the car. Despite many years of study, how this switch works is not understood at a molecular level. Our new data suggest an unanticipated mechanism by which this might occur and we propose to explore these exciting new ideas here.Our approach will combine cellular imaging, X-ray structural analysis and biochemical/biophysical techniques to obtain a full range of biological insights. In the long term we consider it possible that an ability to modulate motor-cargo interactions and motor activity may be gained from these studies could be useful for treatment of a range of human diseases.