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Regulation of KIF1C transport
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Siddiqui, Nida (2018) Regulation of KIF1C transport. PhD thesis, University of Warwick.
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Official URL: http://webcat.warwick.ac.uk/record=b3229869~S15
Abstract
KIF1C is a kinesin-3 family motor protein that accumulates at the tip of the tail in migrating cells and transports α5β1-integrins into cellular protrusions and is therefore required for the regulation of cell adhesion structures. KIF1C also transports dense core vesicles (DCVs) in neurons. Consistent with its function in long distance transport, mutations in KIF1C causes hereditary spastic paraplegia (HSP) and cerebellar dysfunction in humans. Previous data generated in the Straube lab (Bachmann et al, unpublished) show that PTPN21, a scaffolding phosphatase restores KIF1C mediated α5-integrin transport when overexpressed in KIF1C-depleted cells. In this study, the hydrodynamic analysis of recombinant full-length KIF1C and crosslinking mass spectrometry reveals that KIF1C is a stable dimer that adopts an autoinhibited conformation by interaction of its tail with the motor domain. Next, we show that KIF1C is a processive plus-end directed motor in single molecule assays and confirm that the scaffold phosphatase PTPN21 is a positive regulator of KIF1C-mediated transport. We also investigate the structural domains of KIF1C contributing to the rear accumulation in cells and show that the proline rich domain at the C-terminus of KIF1C is required for the tail localisation of KIF1C, but that the binding of 14-3-3 proteins to the tail domain negatively regulates KIF1C. Finally, using optical trapping we show that a single KIF1C can generate forces up to 5.5 pN and the HSP-causing mutations are processive but weak motors.
Item Type: | Thesis (PhD) | ||||
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Subjects: | Q Science > QP Physiology | ||||
Library of Congress Subject Headings (LCSH): | Kinesin, Biological transport, Microtubules, Protein-tyrosine phosphatase, Cell adhesion, Integrins | ||||
Official Date: | January 2018 | ||||
Dates: |
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Institution: | University of Warwick | ||||
Theses Department: | Warwick Medical School | ||||
Thesis Type: | PhD | ||||
Publication Status: | Unpublished | ||||
Supervisor(s)/Advisor: | Straube, Anne ; Cross, R. A. | ||||
Format of File: | |||||
Extent: | viii, 122 leaves : illustrations, charts | ||||
Language: | eng |
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