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Structural basis of the human Scribble–Vangl2 association in health and disease
Scribble is a critical cell polarity regulator that has been shown to work as either an oncogene or tumor suppressor in a context dependent manner, and also impacts cell migration, tissue architecture and immunity. Mutations in Scribble lead to neural tube defects in mice and humans, which has been...
Autores principales: | , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Portland Press Ltd.
2021
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8038854/ https://www.ncbi.nlm.nih.gov/pubmed/33684218 http://dx.doi.org/10.1042/BCJ20200816 |
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author | How, Jing Yuan Stephens, Rebecca K. Lim, Krystle Y.B. Humbert, Patrick O. Kvansakul, Marc |
author_facet | How, Jing Yuan Stephens, Rebecca K. Lim, Krystle Y.B. Humbert, Patrick O. Kvansakul, Marc |
author_sort | How, Jing Yuan |
collection | PubMed |
description | Scribble is a critical cell polarity regulator that has been shown to work as either an oncogene or tumor suppressor in a context dependent manner, and also impacts cell migration, tissue architecture and immunity. Mutations in Scribble lead to neural tube defects in mice and humans, which has been attributed to a loss of interaction with the planar cell polarity regulator Vangl2. We show that the Scribble PDZ domains 1, 2 and 3 are able to interact with the C-terminal PDZ binding motif of Vangl2 and have now determined crystal structures of these Scribble PDZ domains bound to the Vangl2 peptide. Mapping of mammalian neural tube defect mutations reveal that mutations located distal to the canonical PDZ domain ligand binding groove can not only ablate binding to Vangl2 but also disrupt binding to multiple other signaling regulators. Our findings suggest that PDZ-associated neural tube defect mutations in Scribble may not simply act in a Vangl2 dependent manner but as broad-spectrum loss of function mutants by disrupting the global Scribble-mediated interaction network. |
format | Online Article Text |
id | pubmed-8038854 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | Portland Press Ltd. |
record_format | MEDLINE/PubMed |
spelling | pubmed-80388542021-04-19 Structural basis of the human Scribble–Vangl2 association in health and disease How, Jing Yuan Stephens, Rebecca K. Lim, Krystle Y.B. Humbert, Patrick O. Kvansakul, Marc Biochem J Cell Migration, Adhesion & Morphology Scribble is a critical cell polarity regulator that has been shown to work as either an oncogene or tumor suppressor in a context dependent manner, and also impacts cell migration, tissue architecture and immunity. Mutations in Scribble lead to neural tube defects in mice and humans, which has been attributed to a loss of interaction with the planar cell polarity regulator Vangl2. We show that the Scribble PDZ domains 1, 2 and 3 are able to interact with the C-terminal PDZ binding motif of Vangl2 and have now determined crystal structures of these Scribble PDZ domains bound to the Vangl2 peptide. Mapping of mammalian neural tube defect mutations reveal that mutations located distal to the canonical PDZ domain ligand binding groove can not only ablate binding to Vangl2 but also disrupt binding to multiple other signaling regulators. Our findings suggest that PDZ-associated neural tube defect mutations in Scribble may not simply act in a Vangl2 dependent manner but as broad-spectrum loss of function mutants by disrupting the global Scribble-mediated interaction network. Portland Press Ltd. 2021-04-16 2021-04-06 /pmc/articles/PMC8038854/ /pubmed/33684218 http://dx.doi.org/10.1042/BCJ20200816 Text en © 2021 The Author(s) https://creativecommons.org/licenses/by-nc-nd/4.0/This is an open access article published by Portland Press Limited on behalf of the Biochemical Society and distributed under the Creative Commons Attribution License 4.0 (CC BY-NC-ND) (https://creativecommons.org/licenses/by-nc-nd/4.0/) . Open access for this article was enabled by the participation of La Trobe University in an all-inclusive Read & Publish pilot with Portland Press and the Biochemical Society under a transformative agreement with CAUL. |
spellingShingle | Cell Migration, Adhesion & Morphology How, Jing Yuan Stephens, Rebecca K. Lim, Krystle Y.B. Humbert, Patrick O. Kvansakul, Marc Structural basis of the human Scribble–Vangl2 association in health and disease |
title | Structural basis of the human Scribble–Vangl2 association in health and disease |
title_full | Structural basis of the human Scribble–Vangl2 association in health and disease |
title_fullStr | Structural basis of the human Scribble–Vangl2 association in health and disease |
title_full_unstemmed | Structural basis of the human Scribble–Vangl2 association in health and disease |
title_short | Structural basis of the human Scribble–Vangl2 association in health and disease |
title_sort | structural basis of the human scribble–vangl2 association in health and disease |
topic | Cell Migration, Adhesion & Morphology |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8038854/ https://www.ncbi.nlm.nih.gov/pubmed/33684218 http://dx.doi.org/10.1042/BCJ20200816 |
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