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

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...

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Autores principales: Rafiei, Atefeh, Cruz Tetlalmatzi, Sofía, Edrington, Claire H, Lee, Linda, Crowder, D Alex, Saltzberg, Daniel J, Sali, Andrej, Brouhard, Gary, Schriemer, David C
Formato: Online Artículo Texto
Lenguaje:English
Publicado: eLife Sciences Publications, Ltd 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9122500/
https://www.ncbi.nlm.nih.gov/pubmed/35485925
http://dx.doi.org/10.7554/eLife.66975
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author Rafiei, Atefeh
Cruz Tetlalmatzi, Sofía
Edrington, Claire H
Lee, Linda
Crowder, D Alex
Saltzberg, Daniel J
Sali, Andrej
Brouhard, Gary
Schriemer, David C
author_facet Rafiei, Atefeh
Cruz Tetlalmatzi, Sofía
Edrington, Claire H
Lee, Linda
Crowder, D Alex
Saltzberg, Daniel J
Sali, Andrej
Brouhard, Gary
Schriemer, David C
author_sort Rafiei, Atefeh
collection PubMed
description 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-electron microscopy, 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.
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spelling pubmed-91225002022-05-21 Doublecortin engages the microtubule lattice through a cooperative binding mode involving its C-terminal domain Rafiei, Atefeh Cruz Tetlalmatzi, Sofía Edrington, Claire H Lee, Linda Crowder, D Alex Saltzberg, Daniel J Sali, Andrej Brouhard, Gary Schriemer, David C eLife Biochemistry and Chemical Biology 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-electron microscopy, 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. eLife Sciences Publications, Ltd 2022-04-29 /pmc/articles/PMC9122500/ /pubmed/35485925 http://dx.doi.org/10.7554/eLife.66975 Text en © 2022, Rafiei et al https://creativecommons.org/licenses/by/4.0/This article is distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use and redistribution provided that the original author and source are credited.
spellingShingle Biochemistry and Chemical Biology
Rafiei, Atefeh
Cruz Tetlalmatzi, Sofía
Edrington, Claire H
Lee, Linda
Crowder, D Alex
Saltzberg, Daniel J
Sali, Andrej
Brouhard, Gary
Schriemer, David C
Doublecortin engages the microtubule lattice through a cooperative binding mode involving its C-terminal domain
title Doublecortin engages the microtubule lattice through a cooperative binding mode involving its C-terminal domain
title_full Doublecortin engages the microtubule lattice through a cooperative binding mode involving its C-terminal domain
title_fullStr Doublecortin engages the microtubule lattice through a cooperative binding mode involving its C-terminal domain
title_full_unstemmed Doublecortin engages the microtubule lattice through a cooperative binding mode involving its C-terminal domain
title_short Doublecortin engages the microtubule lattice through a cooperative binding mode involving its C-terminal domain
title_sort doublecortin engages the microtubule lattice through a cooperative binding mode involving its c-terminal domain
topic Biochemistry and Chemical Biology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9122500/
https://www.ncbi.nlm.nih.gov/pubmed/35485925
http://dx.doi.org/10.7554/eLife.66975
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