SCRIB1: Human SCRIB1 (1st PDZ domain)
PDB Code: 2W4F
Human Scribble also known as Vartul belongs to the LAP protein family related to Drosophila scribble, with four PDZ domains and 16 leucine rich repeats which control its localization to the basolateral cell membrane. Scribble is ubiquitously expressed and plays essential roles in cell-cell adhesion, apoptosis and cell proliferation.
The phenotype of the circletail mouse, which contains a single base insertion creating a frame shift that leads to premature termination of the Scrb1 protein underlines the importance of Scribble in development. Homozygous mutant mice die perinatally from craniorachischisis - the most severe form of neural tube defect. Mice also develop heart malformations and cardiomyopathy attributable to abnormalities in cardiomyocyte organization within the early heart tube. Similarly, mice carrying the rumpelschtilzchen mutation (I285K) within the leucine-rich repeat region of Scribble resulting in a five-fold reduced expression of Scribble die perinatally as a result of severe morphological defects including craniorachischisis and exencephaly. In addition, epidermal wound healing is defect in those animals.
Scribble has been proposed to act as a tumor suppressor. SCRIB1 is important for cell polarity, loss of which is one of the hallmarks of cancer, and is correlated with more aggressive and invasive cancers. In addition, Scribble is regulated by oncogenic viruses. Interaction of the Scribble PDZ domains with the E6 protein of cancer-causing mucosotropic human papillomaviruses is essential for the ability of these viruses to induce malignant progression.
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