The cell adhesion receptor TMIGD1 recruits Scribble to the basolateral membrane via direct interaction

Abstract Scribble (Scrib) is a multidomain polarity protein and member of the leucine-rich repeat (LRR) and PDZ domain (LAP) protein family. A loss of Scrib expression is associated with disturbed apical-basal polarity and tumor formation. The tumor suppressive activity of Scrib depends on its membrane localization. However, despite the identification of numerous Scrib-interacting proteins, the mechanisms regulating its membrane recruitment are unclear. Here, we identify the cell adhesion receptor TMIGD1 as a membrane anchor of Scrib. TMIGD1 directly interacts with Scrib through a PDZ domain-mediated interaction. We characterize the association of the TMIGD1 C-terminus with each Scrib PDZ domain and describe the crystal structure of the TMIGD1 peptide – Scrib PDZ1 complex. We also find that TMIGD1 recruits Scrib to the lateral membrane domain when the LRR region is absent. Our findings describe a mechanism of Scrib membrane localization and contribute to the understanding of the tumor suppressive activity of Scrib.