Mechanisms of kinesin control by kinesin binding protein
Award Number
BB/V006568/1Programme
Research GrantStatus / Stage
ActiveDates
5 January 2022 -11 February 2025
Duration (calculated)
03 years 01 monthsFunder(s)
BBSRC (UKRI)Funding Amount
£575,405.00Funder/Grant study page
BBSRC UKRIContracted Centre
King's College LondonPrincipal Investigator
Dr Joseph AthertonPI Contact
joseph.atherton@kcl.ac.ukPI ORCID
0000-0002-6362-2347WHO Catergories
Understanding Underlying DiseaseDisease Type
Dementia (Unspecified)CPEC Review Info
| Reference ID | 689 |
|---|---|
| Researcher | Reside Team |
| Published | 07/07/2023 |
Data
| Award Number | BB/V006568/1 |
|---|---|
| Status / Stage | Active |
| Start Date | 20220105 |
| End Date | 20250211 |
| Duration (calculated) | 03 years 01 months |
| Funder/Grant study page | BBSRC UKRI |
| Contracted Centre | King's College London |
| Funding Amount | £575,405.00 |
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.
Aims
This project aims to reveal the mechanisms behind KBP’s kinesin member selectivity and inhibition and KBP regulation.