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Mechanisms of kinesin control by kinesin binding protein

Reference	BB/V006568/1
Principal Investigator / Supervisor	Dr Joseph Atherton
Co-Investigators / Co-Supervisors
Institution	King's College London
Department	Randall Div of Cell and Molecular Biophy
Funding type	Research
Value (£)	575,405
Status	Current
Type	Research Grant
Start date	05/01/2022
End date	11/02/2025
Duration	37 months

Abstract

Kinesin family molecular motors play essential roles during cell division, differentiation, and maturity, distributing cellular cargo and organising microtubule (MT) networks. In dividing cells, they are essential force providers, MT organisers and signalling hubs. In cell development and plasticity, they reorganise the MT scaffolding and specialise cellular subdomains with targeted cargo delivery. Kinesin dysregulation has been implicated in a wide range of animal and plant pathologies. Kinesin activity is tightly regulated in time and space by auto-inhibitory conformations, post-translational modifications and co-factor binding. Kinesin-binding protein (KBP) is an important, yet poorly understood regulatory co-factor found in early eukaryotes to humans that binds a subset of kinesin motor domains to inhibit MT association. Crucial roles for KBP have been identified in a variety of cellular processes including mitosis, organelle distribution, spermatogenesis and neuronal development. Illustrating KBP's importance, gene variants cause Goldberg-Shprintzen syndrome and determine neuroblastoma prognosis. Despite the importance of KBP in eukaryotic cell fundamentals, the mechanisms behind KBP's selective kinesin inhibitory function remain unknown. Furthermore, it is unclear how KBP is regulated itself, in order to temporally and spatially manage selected kinesin activities. This project aims to reveal the mechanisms behind KBP's kinesin member selectivity and inhibition and KBP regulation. Towards these aims, the revolutionary structural technique of cryo-electron microscopy will be used alongside supporting methods to characterise KBP interactions with various kinesin motor domains, autoinhibited kinesins and active kinesin dimers as well as the modulation of these interactions by phosphorylation. Unearthing KBP's mechanisms will fill a void in our understanding of kinesin regulation, a central aspect of eukaryotic cell function.

Summary

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.

Committee	Research Committee D (Molecules, cells and industrial biotechnology)
Research Topics	Structural Biology
Research Priority	X – Research Priority information not available
Research Initiative	X - not in an Initiative
Funding Scheme	X – not Funded via a specific Funding Scheme

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