Cell polarity, the process of uneven distribution of macromolecules within the cell, is essential in maintaining cellular architecture and connection. It has been linked with cancer development due to cell polarity dysregulation by protein mislocalisation [1,2]. Scribble, a cell polarity protein, is often mislocalised during cancer progression. Its role as an adaptor protein relies on the four PDZ domains which are essential in protein-protein interaction and each domain has a different binding specificity which enables them to interact with several Scribble binding partners [2,4]. Therefore, it is with great interest to understand how Scribble facilitates its interactions along with the significance of these interactions through a quantitative approach.
Previous studies demonstrated that Scribble has interactions with the planar cell polarity protein Vangl2, utilizing Scribble PDZ2 and PDZ3 [3]. Affinity measurements using isothermal titration calorimetry in this study however, demonstrated that all PDZ domains except PDZ4 has shown interaction with the binding partners with affinities in the micromolar range. To understand the structural basis of Scribble PDZ domain interactions with Vangl2, the interacting complexes were crystallized, and structures of individual PDZ domains with Vangl2 C-terminal peptide were determined. By comparing the PDZ-Vangl2 complex structures with Scribble PDZ domain structures from previous studies [5.6], the mode of binding, as well as the PDZ domain residues involved in binding, are conserved despite the difference in binding partners and organisms where the Scribble PDZ domains derive from.
These findings will serve as a platform to understand the role of Scribble PDZ domains in cell polarity regulation at the atomic level, and inform future mutagenesis experiments to delineate how individual Scribble PDZ domains contribute to these interactions.