Mechanisms of MAGUK-mediated cellular junctional complex organization

•The GK domain of MAGUKs has evolved from a nucleotide kinase into a versatile protein binding module.•MAGUK GKs can bind to both phosphorylated and non-phosphorylated target proteins.•The PDZ-SH3-GK tandem of MAGUKs forms a structural and functional supramodule.•MAGUKs are capable of organizing very large signalsomes via multimerization of the PDZ-SH3-GK tandems.

Membrane-associated guanylate kinases (MAGUKs) are a family of scaffold proteins that are enriched in cellular junctions and essential for tissue development and homeostasis. Mutations of MAGUKs are linked to many human diseases including cancers, psychiatric disorders, and intellectual disabilities. MAGUKs share a common PDZ-SH3-GK tandem domain organization at the C-terminal end. In this review, we summarize the mechanistic basis governing target recognition and regulations of this binding by the PDZ-SH3-GK tandem of various MAGUKs. We also discuss recent discoveries showing unique folding features of MAGUK PDZ-SH3-GK tandems that facilitate ligand-induced oligomerization of MAGUKs and phase transition of MAGUK-assembled synaptic signaling complexes.