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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...

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Autores principales: How, Jing Yuan, Stephens, Rebecca K., Lim, Krystle Y.B., Humbert, Patrick O., Kvansakul, Marc
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Portland Press Ltd. 2021
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.
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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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