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.

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.

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