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...
| Main Authors: | , , , , , , , , |
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| Format: | Article |
| Language: | English |
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eLife Sciences Publications Ltd
2022-04-01
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| Series: | eLife |
| Subjects: | |
| Online Access: | https://elifesciences.org/articles/66975 |
| _version_ | 1811252714799104000 |
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| author | Atefeh Rafiei Sofía Cruz Tetlalmatzi Claire H Edrington Linda Lee D Alex Crowder Daniel J Saltzberg Andrej Sali Gary Brouhard David C Schriemer |
| author_facet | Atefeh Rafiei Sofía Cruz Tetlalmatzi Claire H Edrington Linda Lee D Alex Crowder Daniel J Saltzberg Andrej Sali Gary Brouhard David C Schriemer |
| author_sort | Atefeh Rafiei |
| collection | DOAJ |
| 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. |
| first_indexed | 2024-04-12T16:39:49Z |
| format | Article |
| id | doaj.art-c0c1f63c70ab443d8a4198aa65ca6e7b |
| institution | Directory Open Access Journal |
| issn | 2050-084X |
| language | English |
| last_indexed | 2024-04-12T16:39:49Z |
| publishDate | 2022-04-01 |
| publisher | eLife Sciences Publications Ltd |
| record_format | Article |
| series | eLife |
| spelling | doaj.art-c0c1f63c70ab443d8a4198aa65ca6e7b2022-12-22T03:24:52ZengeLife Sciences Publications LtdeLife2050-084X2022-04-011110.7554/eLife.66975Doublecortin engages the microtubule lattice through a cooperative binding mode involving its C-terminal domainAtefeh Rafiei0Sofía Cruz Tetlalmatzi1Claire H Edrington2Linda Lee3D Alex Crowder4Daniel J Saltzberg5Andrej Sali6https://orcid.org/0000-0003-0435-6197Gary Brouhard7https://orcid.org/0000-0001-9101-1247David C Schriemer8https://orcid.org/0000-0002-5202-1618Department of Chemistry, University of Calgary, Calgary, CanadaDepartment of Biology, McGill University, Montréal, CanadaDepartment of Biology, McGill University, Montréal, CanadaDepartment of Biochemistry and Molecular Biology, University of Calgary, Calgary, CanadaDepartment of Biochemistry and Molecular Biology, University of Calgary, Calgary, CanadaDepartment of Bioengineering and Therapeutic Sciences, University of California, San Francisco, San Francisco, United StatesDepartment of Bioengineering and Therapeutic Sciences, University of California, San Francisco, San Francisco, United States; Department of Pharmaceutical Chemistry, California Institute for Quantitative Biosciences, University of California, San Francisco, San Francisco, United StatesDepartment of Biology, McGill University, Montréal, CanadaDepartment of Chemistry, University of Calgary, Calgary, Canada; Department of Biochemistry and Molecular Biology, University of Calgary, Calgary, CanadaDoublecortin (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.https://elifesciences.org/articles/66975Doublecortinmicrotubulesneuronsmass spectrometryintegrative modelingelectron microscopy |
| spellingShingle | Atefeh Rafiei Sofía Cruz Tetlalmatzi Claire H Edrington Linda Lee D Alex Crowder Daniel J Saltzberg Andrej Sali Gary Brouhard David C Schriemer Doublecortin engages the microtubule lattice through a cooperative binding mode involving its C-terminal domain eLife Doublecortin microtubules neurons mass spectrometry integrative modeling electron microscopy |
| 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 | Doublecortin microtubules neurons mass spectrometry integrative modeling electron microscopy |
| url | https://elifesciences.org/articles/66975 |
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