Cell polarity is an essential property of cells critical for maintaining cellular integrity, and cell polarity deregulation by protein mislocalisation has been linked to numerous disease states, most notably cancer. Scribble, a cell polarity protein, is often mislocalised during cancer progression. Its role as an adaptor protein relies on the PDZ domains of Scribble 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. Previous studies demonstrated that Scribble interacts with the planar cell polarity protein Vangl2 through Scribble PDZ2 and PDZ3 domains. Affinity measurements using isothermal titration calorimetry in this study however demonstrated that Vangl2 binds to recombinant Scribble PDZ1 domain as well as Scribble PDZ2 and PDZ3 domains, with all three PDZ domains interacting with Vangl2 with similar binding affinities. Intriguingly, despite the presence of three functional binding sites amongst the four Scribble PDZ domains, only a single binding site is utilized when Vangl2 binds a constructs comprising all four Scribble PDZ domains, suggesting the supertertiary structure of Scribble regulates binding to Vangl2. To understand the structural basis of Scribble PDZ domain interactions with Vangl2, complexes of Scribble PDZ2 and PDZ3 with Vangl2 were crystallised, and the structure of the PDZ3-Vangl2 complex was determined. These findings will serve as a platform to understand the role of Scribble PDZ domains in Vangl2 meditated cell polarity control at the atomic level, and inform future mutagenesis experiments to delineate how individual Scribble PDZ domains contribute to Scribble-Vangl2 interactions.