Mechanistic basis for co-operativity in kinesin-1 / cargo recognition

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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. They can also control the organisation of the network itself by sliding against one another. 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 and how this in turn controls the behaviour of the motor. This joint proposal stems from a sustained successful partnership between the Dodding group, now at the School of Biochemistry of the University of Bristol and the Steiner group of the Randall Centre of Cell and Molecular Biophysics, King's College London. To date, their fruitful collaborative work has highlighted important aspects of how kinesin-1 attaches to the cellular components it carries (using protein-peptide interactions) and how these connections in turn control how kinesin-1 moves. Importantly, they have used this knowledge to identify small molecules (drug-like chemicals) that have allowed us to directly manipulate this system in cells for the first time. These exciting findings have now promoted a series of new questions that will be addressed here. Until now, our studies have focused on defining quite simple and straightforward connections between kinesin-1 and its cargoes. However, it is becoming clear that this is only part of the picture and that this process requires multiple connections between kinesin-1 and its cargoes that work together. We propose that the precise nature of these 'co-operative' connections determines how transport works. Here we will explore how kinesin-1 can interact directly with the surface of membrane bound organelles (by attaching to membrane lipids) and how these connections work together with those we have already defined. Moreover, collections of proteins can interact with each other and kinesin-1 - we will seek to define those connections on a molecular level. We will continue to use the knowledge we acquire to further chemically manipulate this cargo attachment system to see if we can target specific aspects of kinesin-1 function. It is possible that in the long term, this may show how we can develop drugs to target kinesin-1 in human disease.