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Novel septin 9 repeat motifs altered in neuralgic amyotrophy bind and bundle microtubules

Septin 9 (SEPT9) interacts with microtubules (MTs) and is mutated in hereditary neuralgic amyotrophy (HNA), an autosomal-dominant neuropathy. The mechanism of SEPT9 interaction with MTs and the molecular basis of HNA are unknown. Here, we show that the N-terminal domain of SEPT9 contains the novel r...

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Autores principales: Bai, Xiaobo, Bowen, Jonathan R., Knox, Tara K., Zhou, Kaifeng, Pendziwiat, Manuela, Kuhlenbäumer, Gregor, Sindelar, Charles V., Spiliotis, Elias T.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: The Rockefeller University Press 2013
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3871440/
https://www.ncbi.nlm.nih.gov/pubmed/24344182
http://dx.doi.org/10.1083/jcb.201308068
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author Bai, Xiaobo
Bowen, Jonathan R.
Knox, Tara K.
Zhou, Kaifeng
Pendziwiat, Manuela
Kuhlenbäumer, Gregor
Sindelar, Charles V.
Spiliotis, Elias T.
author_facet Bai, Xiaobo
Bowen, Jonathan R.
Knox, Tara K.
Zhou, Kaifeng
Pendziwiat, Manuela
Kuhlenbäumer, Gregor
Sindelar, Charles V.
Spiliotis, Elias T.
author_sort Bai, Xiaobo
collection PubMed
description Septin 9 (SEPT9) interacts with microtubules (MTs) and is mutated in hereditary neuralgic amyotrophy (HNA), an autosomal-dominant neuropathy. The mechanism of SEPT9 interaction with MTs and the molecular basis of HNA are unknown. Here, we show that the N-terminal domain of SEPT9 contains the novel repeat motifs K/R-x-x-E/D and R/K-R-x-E, which bind and bundle MTs by interacting with the acidic C-terminal tails of β-tubulin. Alanine scanning mutagenesis revealed that the K/R-R/x-x-E/D motifs pair electrostatically with one another and the tails of β-tubulin, enabling septin–septin interactions that link MTs together. SEPT9 isoforms lacking repeat motifs or containing the HNA-linked mutation R88W, which maps to the R/K-R-x-E motif, diminished intracellular MT bundling and impaired asymmetric neurite growth in PC-12 cells. Thus, the SEPT9 repeat motifs bind and bundle MTs, and thereby promote asymmetric neurite growth. These results provide the first insight into the mechanism of septin interaction with MTs and the molecular and cellular basis of HNA.
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spelling pubmed-38714402014-06-23 Novel septin 9 repeat motifs altered in neuralgic amyotrophy bind and bundle microtubules Bai, Xiaobo Bowen, Jonathan R. Knox, Tara K. Zhou, Kaifeng Pendziwiat, Manuela Kuhlenbäumer, Gregor Sindelar, Charles V. Spiliotis, Elias T. J Cell Biol Research Articles Septin 9 (SEPT9) interacts with microtubules (MTs) and is mutated in hereditary neuralgic amyotrophy (HNA), an autosomal-dominant neuropathy. The mechanism of SEPT9 interaction with MTs and the molecular basis of HNA are unknown. Here, we show that the N-terminal domain of SEPT9 contains the novel repeat motifs K/R-x-x-E/D and R/K-R-x-E, which bind and bundle MTs by interacting with the acidic C-terminal tails of β-tubulin. Alanine scanning mutagenesis revealed that the K/R-R/x-x-E/D motifs pair electrostatically with one another and the tails of β-tubulin, enabling septin–septin interactions that link MTs together. SEPT9 isoforms lacking repeat motifs or containing the HNA-linked mutation R88W, which maps to the R/K-R-x-E motif, diminished intracellular MT bundling and impaired asymmetric neurite growth in PC-12 cells. Thus, the SEPT9 repeat motifs bind and bundle MTs, and thereby promote asymmetric neurite growth. These results provide the first insight into the mechanism of septin interaction with MTs and the molecular and cellular basis of HNA. The Rockefeller University Press 2013-12-23 /pmc/articles/PMC3871440/ /pubmed/24344182 http://dx.doi.org/10.1083/jcb.201308068 Text en © 2013 Bai et al. https://creativecommons.org/licenses/by-nc-sa/3.0/This article is distributed under the terms of an Attribution–Noncommercial–Share Alike–No Mirror Sites license for the first six months after the publication date (see http://www.rupress.org/terms). After six months it is available under a Creative Commons License (Attribution–Noncommercial–Share Alike 3.0 Unported license, as described at http://creativecommons.org/licenses/by-nc-sa/3.0/ (https://creativecommons.org/licenses/by-nc-sa/3.0/) ).
spellingShingle Research Articles
Bai, Xiaobo
Bowen, Jonathan R.
Knox, Tara K.
Zhou, Kaifeng
Pendziwiat, Manuela
Kuhlenbäumer, Gregor
Sindelar, Charles V.
Spiliotis, Elias T.
Novel septin 9 repeat motifs altered in neuralgic amyotrophy bind and bundle microtubules
title Novel septin 9 repeat motifs altered in neuralgic amyotrophy bind and bundle microtubules
title_full Novel septin 9 repeat motifs altered in neuralgic amyotrophy bind and bundle microtubules
title_fullStr Novel septin 9 repeat motifs altered in neuralgic amyotrophy bind and bundle microtubules
title_full_unstemmed Novel septin 9 repeat motifs altered in neuralgic amyotrophy bind and bundle microtubules
title_short Novel septin 9 repeat motifs altered in neuralgic amyotrophy bind and bundle microtubules
title_sort novel septin 9 repeat motifs altered in neuralgic amyotrophy bind and bundle microtubules
topic Research Articles
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3871440/
https://www.ncbi.nlm.nih.gov/pubmed/24344182
http://dx.doi.org/10.1083/jcb.201308068
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