6xa8
From Proteopedia
Crystal Structure of Human Scribble PDZ1:Vangl2 complex
Structural highlights
DiseaseVANG2_HUMAN Thoracolumbosacral spina bifida cystica;Cervicothoracic spina bifida cystica;Lumbosacral spina bifida cystica;Cervicothoracic spina bifida aperta;Upper thoracic spina bifida aperta;Lumbosacral spina bifida aperta;Thoracolumbosacral spina bifida aperta;Cervical spina bifida cystica;Upper thoracic spina bifida cystica;Isolated exencephaly;Total spina bifida aperta;Total spina bifida cystica;Isolated anencephaly;Cervical spina bifida aperta. The disease is caused by variants affecting the gene represented in this entry. FunctionVANG2_HUMAN Involved in the control of early morphogenesis and patterning of both axial midline structures and the development of neural plate. Plays a role in the regulation of planar cell polarity, particularly in the orientation of stereociliary bundles in the cochlea. Required for polarization and movement of myocardializing cells in the outflow tract and seems to act via RHOA signaling to regulate this process. Required for cell surface localization of FZD3 and FZD6 in the inner ear (By similarity).[UniProtKB:Q91ZD4] Publication Abstract from PubMedScribble 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. Structural basis of the human Scribble-Vangl2 association in health and disease.,How JY, Stephens R, Lim KYB, Humbert PO, Kvansakul M Biochem J. 2021 Mar 8. pii: 228041. doi: 10.1042/BCJ20200816. PMID:33684218[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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