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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...
Autores principales: | , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
eLife Sciences Publications, Ltd
2022
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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. |
format | Online Article Text |
id | pubmed-9122500 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | eLife Sciences Publications, Ltd |
record_format | MEDLINE/PubMed |
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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