PALS1 (protein associated with LIN7 1) is a scaffold protein and member of the p55 MAGUK family that plays a crucial role in establishing and maintaining epithelial cell polarity and tight junction formation 1. The protein functions as part of the evolutionary conserved CRUMBS/PALS1/PATJ polarity complex, which is essential for developing the apico-basal axis in epithelial cells 1. PALS1 contains a PDZ domain that mediates protein-protein interactions, particularly binding to the Crumbs (CRB) transmembrane protein through a gated access mechanism involving a key phenylalanine residue 2. In disease contexts, PALS1 serves as a tumor suppressor in colorectal cancer, where its downregulation correlates with poorer patient survival and increased metastasis through Rac1-dependent cell migration via Arf6 activation 3. Additionally, PALS1 acts as an interaction partner for SARS-CoV and SARS-CoV-2 envelope proteins, with SARS-CoV-2 showing higher binding affinity, potentially contributing to viral pathogenesis by disrupting tight junction formation and cell polarity 4. The protein also regulates solute carrier transporter expression in the kidney, and its haploinsufficiency leads to renal cysts and proteinuria 5.