Mechanisms of kinesin control by kinesin binding protein

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In all our cells molecular motor-like machines known as kinesins walk along filaments called microtubules in order to deliver cargos to subregions upon demand. Furthermore, kinesins can reorganise the arrangement and length of microtubules themselves. These kinesin functions are particularly important in cell division and in establishing the complex, compartmentalised nature of specialised animal cells. During cell division kinesins are vital for creating the forces and microtubule arrangements required to drive genetic material apart. In cellular development and specialisation kinesins rearrange the microtubule scaffolding and make sure subcompartment components are delivered upon demand. In fact, kinesins are fundamental in most of our body's workings, including the maintenance and remodelling of nerve cells behind consciousness, learning and memory. Accordingly given their vital functions, abnormalities in kinesin activity are implicated in a number of illnesses, from cancer to dementia.In order to orchestrate the activity of particular kinesin motors in designated cellular subdomains and at required times, cells have employed a number of kinesin control mechanisms. An exciting kinesin regulator, known as kinesin-binding protein (KBP) has been shown to prevent microtubule attachment and movement of specific subtypes of kinesins. KBP-based regulation of kinesins is being implicated in an expanding list of areas, including brain and heart development, cell division, nerve cell functioning and sperm construction. Altered KBP function has been shown to cause a debilitating neurodevelopmental condition known as Goldberg-Shprintzen syndrome, as well as decrease survival rates in neuroblastoma, a childhood cancer. Given the importance of KBP and its kinesin targets, KBP is poorly understood. It is crucial to understand how KBP prevents the microtubule attachment and motility of kinesins, how it selects particular kinesin subtypes and how the actions of KBP itself are controlled. The proposed project aims to use the cutting-edge Nobel prize winning technique of cryo-electron microscopy to acquire detailed 3D architectural descriptions of KBP interactions with kinesins and regulatory partners, in order to answer these questions. Cryo-electron microscopy can be used to study the dynamic structures of molecular machines in near-native conditions, using the enhanced resolving power of electrons over light for unrivalled detail. The technique has undergone a recent technological and theoretical revolution, enabling routine atomic-level molecular detail leading to unique discoveries. Apart from enhancing our understanding of kinesin and KBP-based biological processes, a better characterisation of KBP will help describe its role in kinesin and KBP-associated illnesses, potentially leading to new therapeutics.