Doublecortin engages the microtubule lattice through a cooperative binding mode involving its C-terminal domain
- University of Calgary, Canada
- McGill University, Canada
- University of California, San Francisco, United States
Abstract
Doublecortin (DCX) is a microtubule (MT) associated protein that regulates MT structure and function during neuronal development and mutations in DCX lead to a spectrum of neurological disorders. The structural properties of MT-bound DCX that explain these disorders are incompletely determined. Here, we describe the molecular architecture of the DCX-MT complex through an integrative modeling approach that combines data from X-ray crystallography, cryo-EM and a high-fidelity chemical crosslinking method. We demonstrate that DCX interacts with MTs through its N-terminal domain and induces a lattice-dependent self-association involving the C-terminal structured domain and its disordered tail, in a conformation that favors an open, domain-swapped state. The networked state can accommodate multiple different attachment points on the MT lattice, all of which orient the C-terminal tails away from the lattice. As numerous disease mutations cluster in the C-terminus, and regulatory phosphorylations cluster in its-tail, our study shows that lattice-driven self-assembly is an important property of DCX.
Data availability
The DCX-MT integrative models, including final structures, modeling details, and input experimental data, were deposited into the PDB-dev repository for integrative models (www.pdb-dev.com) as follows: Dimeric DCX-MT (diagonal1): PDBDEV_00000071 Dimeric DCX-MT (lateral): PDBDEV_00000072 Dimeric DCX-MT (longitudinal): PDBDEV_00000073 Dimeric DCX-MT (diagonal2): PDBDEV_00000074 All LC-MS/MS data generated to support the findings of this study have been deposited with the ProteomeXchange Consortium with the dataset identifier PXD033167.
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DCX-MT crosslinkingProteomeXchange, PXD033167.
Article and author information
Author details
Funding
Canarie (RS-326)
- David C Schriemer
Natural Sciences and Engineering Research Council of Canada (RGPIN-2017-04879)
- David C Schriemer
Natural Sciences and Engineering Research Council of Canada (RGPIN-2020-04876)
- Gary Brouhard
Canadian Institutes of Health Research (PJT-148702)
- Gary Brouhard
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Copyright
© 2022, Rafiei et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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Doublecortin engages the microtubule lattice through a cooperative binding mode involving its C-terminal domain
eLife 11:e66975.
https://doi.org/10.7554/eLife.66975
