期刊
BIOCHEMICAL JOURNAL
卷 478, 期 7, 页码 1321-1332出版社
PORTLAND PRESS LTD
DOI: 10.1042/BCJ20200816
关键词
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资金
- National Health and Medical Research Council Australia [APP1103871, APP1079133]
- Australian Research Council [FT130101349]
- La Trobe University [2000002510]
Scribble is a critical cell polarity regulator, and mutations in it lead to neural tube defects. Research shows that these mutations not only affect binding to Vangl2, but also disrupt binding to multiple other signaling regulators.
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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