Mosby, Lewis S. (2021) How microtubule +TIP trackers couple polymer assembly to cargo transport. PhD thesis, University of Warwick.

PDF WRAP_Theses_Mosby_2021.pdf - Submitted Version Embargoed item. Restricted access to Repository staff only until 10 January 2024. Contact author directly, specifying your specific needs. - Requires a PDF viewer. Download (16Mb)

Request Changes to record.

Abstract

End-binding proteins (EBs) are specialised proteins that can autonomously track growing microtubule ends whilst recruiting other proteins (+TIPs). By interacting with STIM1, a transmembrane protein associated with the endoplasmic reticulum (ER), EBs are able to mediate ER re-organisation and tubulation. Intracellular transport is vital for achieving the correct distribution of organelles. This work aims to derive an analytical model that can explain how transiently binding proteins can couple microtubule growth to the motion of cargo inside cells.

It will be shown in this work that EBs exhibit a dwell time distribution that is best _t by a superposition of two exponential decay functions, which indicates multistate binding behaviour. An analytical model has been developed that reproduces these binding dynamics. Once expanded to study cargo permanently bound to multiple EBs, this model is able to predict the phenomenon of tip tracking as a response to position dependence in the EB-microtubule binding rate distribution. Using experimentally-derived input parameters, it will be shown that the resulting effective velocity exhibited by cargo acts towards the growing ends of microtubules and can be of similar magnitude to the microtubule growth velocity. Simulated cargo exhibit the same qualitative behaviour as multivalent cargo studied in vitro. Finally, it will be shown that cargo-EB interactions act to inhibit the tip tracking capabilities of cargo by reducing their average dwell time and the magnitude of their effective velocity. This work details one method by which cells can utilise the stochasticity of individual protein dynamics to generate predictable large scale behaviour.

Item Type:	Thesis or Dissertation (PhD)
Subjects:	Q Science > QH Natural history Q Science > QP Physiology
Library of Congress Subject Headings (LCSH):	Microtubules, Protein binding, Membrane proteins, Biological transport, Endoplasmic reticulum
Official Date:	April 2021
Dates:	Date Event April 2021 UNSPECIFIED
Institution:	University of Warwick
Theses Department:	Warwick Medical School ; Department of Physics
Thesis Type:	PhD
Publication Status:	Unpublished
Supervisor(s)/Advisor:	Straube, Anne ; Polin, Marco
Sponsors:	Leverhulme Trust ; Wellcome Trust (London, England)
Format of File:	pdf
Extent:	xxi, 226 leaves : illustrations
Language:	eng

Request changes or add full text files to a record

Repository staff actions (login required)

View Item