BIROn - Birkbeck Institutional Research Online

    Pseudo-repeats in doublecortin make distinct mechanistic contributions to mi-crotubule regulation

    Manka, Szymon and Moores, Carolyn A. (2020) Pseudo-repeats in doublecortin make distinct mechanistic contributions to mi-crotubule regulation. EMBO Reports (e51534), ISSN 1469-3178.

    [img] Text
    40955.pdf - Author's Accepted Manuscript
    Restricted to Repository staff only

    Download (463kB) | Request a copy
    [img] Text
    40955a.pdf - Supplemental Material
    Restricted to Repository staff only

    Download (2MB) | Request a copy
    [img] Archive
    40955b.zip - Supplemental Material
    Restricted to Repository staff only

    Download (95MB) | Request a copy
    [img]
    Preview
    Text
    40955c.pdf - Published Version of Record
    Available under License Creative Commons Attribution.

    Download (10MB) | Preview

    Abstract

    Doublecortin (DCX) is a neuronal microtubule-associated protein (MAP) indispensable for brain development. Its flexibly linked doublecortin (DC) domains – NDC and CDC – mediate microtubule (MT) nucleation and stabilization, but it is unclear how. Using high-resolution time-resolved cryo-EM, we mapped NDC and CDC interactions with tubulin at different MT polymerization stages and studied their functional effects on MT dynamics using TIRF micros-copy. Although coupled, each DC repeat within DCX appears to have a distinct role in MT nucleation and stabilization: CDC is a conformationally plastic module that appears to facili-tate MT nucleation and stabilize tubulin-tubulin contacts in the nascent MT lattice, while NDC appears to be favoured along the mature lattice, providing MT stabilization. Our struc-tures of MT-bound DC domains also explain in unprecedented detail the DCX mutation-related brain defects observed in the clinic. This modular composition of DCX reflects a com-mon design principle among MAPs where pseudo-repeats of tubulin/MT binding elements chaperone or stabilize distinct conformational transitions to regulate distinct stages of MT dynamic instability.

    Metadata

    Item Type: Article
    Keyword(s) / Subject(s): cryo-EM, doublecortin, DCX domain, microtubule-associated protein, pseudo-repeat
    School: School of Science > Biological Sciences
    Depositing User: Administrator
    Date Deposited: 08 Oct 2020 10:34
    Last Modified: 04 Dec 2020 18:26
    URI: https://eprints.bbk.ac.uk/id/eprint/40955

    Statistics

    Downloads
    Activity Overview
    11Downloads
    14Hits

    Additional statistics are available via IRStats2.

    Archive Staff Only (login required)

    Edit/View Item Edit/View Item