BIROn - Birkbeck Institutional Research Online

    The investigation of the microtubule binding of human doublecortin-like kinase and microtubule dynamics, by cryo-electron microscopy and cryo-electron tomography

    Foran, Tom (2022) The investigation of the microtubule binding of human doublecortin-like kinase and microtubule dynamics, by cryo-electron microscopy and cryo-electron tomography. PhD thesis, Birkbeck, University of London.

    [img]
    Preview
    Text
    The investigation of the microtubule binding of human doublecortin-like kinase and microtubule dynamics, by cryo-electron microscopy and cryo-electron tomography - Tom Foran - 12092022.pdf - Full Version

    Download (107MB) | Preview

    Abstract

    The microtubule (MT) cytoskeleton forms a complex and dynamic network which facilitates important processes such as intracellular signalling, vesicular transport, cell motility and cell division. The cell exerts fine control over the MT cytoskeleton through diverse regulatory mechanisms, one facet of which is through the activities of MT associated proteins (MAPs), which bind MTs and modify their behaviour. Doublecortin (DCX) and doublecortin-like kinase (DCLK) are members of the DCX family of MAPs and contain tandem MT binding domains, NDC and CDC, which allow them to nucleate, bind and stabilize MTs. DCX is involved in the proper migration of cortical neurons during neurogenesis, and dysfunction of DCX and its relatives are implicated in a range of disorders associated with improper neuronal function. DCLK shows remarkable similarity in sequence and fold to its family archetype DCX but surprisingly, we have found that it appears to bind MTs by a different mechanism. Cryo-EM reconstructions of MT-bound DCLK at different timepoints post-nucleation, at near atomic resolution, show that the CDC domain predominates on the mature MT lattice, where NDC predominates in DCX. This raises interesting questions around the nature of the DC domain tandems in DCLK and the other members of the DCX family. In addition, I investigated the link between MT dynamics and + end tip morphology, by cryo-electron tomography. While more work is required here, the preliminary results suggest that there may indeed be different distributions of +end tip morphologies which occur in populations of MTs with different dynamic characteristics.

    Metadata

    Item Type: Thesis
    Copyright Holders: The copyright of this thesis rests with the author, who asserts his/her right to be known as such according to the Copyright Designs and Patents Act 1988. No dealing with the thesis contrary to the copyright or moral rights of the author is permitted.
    Depositing User: Acquisitions And Metadata
    Date Deposited: 13 Dec 2022 15:47
    Last Modified: 01 Nov 2023 15:55
    URI: https://eprints.bbk.ac.uk/id/eprint/50214
    DOI: https://doi.org/10.18743/PUB.00050214

    Statistics

    Activity Overview
    6 month trend
    46Downloads
    6 month trend
    75Hits

    Additional statistics are available via IRStats2.

    Archive Staff Only (login required)

    Edit/View Item Edit/View Item