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Doublecortin engages the microtubule lattice through a cooperative binding mode involving its C-terminal domain

Atefeh Rafiei, Linda Lee, D. Alex Crowder, Daniel J. Saltzberg, View ORCID ProfileAndrej Sali, View ORCID ProfileGary J. Brouhard, View ORCID ProfileDavid C. Schriemer
doi: https://doi.org/10.1101/2021.02.17.431714
Atefeh Rafiei
1Department of Chemistry, University of Calgary, Calgary, Alberta, Canada
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Linda Lee
2Department of Biochemistry and Molecular Biology, University of Calgary, Alberta, Canada
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D. Alex Crowder
2Department of Biochemistry and Molecular Biology, University of Calgary, Alberta, Canada
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Daniel J. Saltzberg
3Department of Bioengineering and Therapeutic Sciences, University of California, San Francisco, CA 94158, USA
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Andrej Sali
3Department of Bioengineering and Therapeutic Sciences, University of California, San Francisco, CA 94158, USA
4Department of Pharmaceutical Chemistry, California Institute for Quantitative Biosciences, University of California, San Francisco, CA 94158, USA
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Gary J. Brouhard
5Dept. of Biology, McGill University, Montreal, Quebec, Canada
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David C. Schriemer
1Department of Chemistry, University of Calgary, Calgary, Alberta, Canada
2Department of Biochemistry and Molecular Biology, University of Calgary, Alberta, Canada
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  • For correspondence: dschriem@ucalgary.ca
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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 remain poorly resolved. 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 both the C-terminal structured domain and the C-tails, 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-tails away from the lattice. As numerous disease mutations cluster in the C-terminus, and regulatory phosphorylations cluster in the C-tail, our study shows that lattice-driven self-assembly is an important property of DCX.

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The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY 4.0 International license.
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Posted February 18, 2021.
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Doublecortin engages the microtubule lattice through a cooperative binding mode involving its C-terminal domain
Atefeh Rafiei, Linda Lee, D. Alex Crowder, Daniel J. Saltzberg, Andrej Sali, Gary J. Brouhard, David C. Schriemer
bioRxiv 2021.02.17.431714; doi: https://doi.org/10.1101/2021.02.17.431714
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Doublecortin engages the microtubule lattice through a cooperative binding mode involving its C-terminal domain
Atefeh Rafiei, Linda Lee, D. Alex Crowder, Daniel J. Saltzberg, Andrej Sali, Gary J. Brouhard, David C. Schriemer
bioRxiv 2021.02.17.431714; doi: https://doi.org/10.1101/2021.02.17.431714

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