The Structure of the PDZ3-SH3-GuK Tandem of ZO-1 Protein Suggests a Supramodular Organization of the Membrane-associated Guanylate Kinase (MAGUK) Family Scaffold Protein Core

Membrane-associated guanylate kinases (MAGUKs) are a large family of scaffold proteins that play essential roles in tethering membrane receptors, adhesion molecules, and macromolecular signaling complexes for tissue developments, cell-cell communications, and intracellular signal transductions. The defining feature of the MAGUK family scaffolds is that each member contains a conserved core consisting of a PSD-95/Dlg/ZO-1 (PDZ) domain, an Src homology 3 (SH3) domain, and a catalytically inactive guanylate kinase (GuK) domain arranged in tandem, although the structural features and functional implications of the PDZ-SH3-GuK tandem arrangement are unclear. The structure of the ZO-1 PDZ3-SH3-GuK tandem solved in this study reveals that the PDZ domain directly interacts with the SH3-GuK module, forming a structural supramodule with distinct target binding properties with respect to the isolated domains. Structure-based sequence analysis suggests that the PDZ-SH3-GuK tandems of other members of the MAGUK family also form supramodules. Background: Every member of MAGUKs contains a sequentially organized PDZ-SH3-GuK tandem, although with unknown structural and functional implications. Results: The structure of ZO-1 PDZ3-SH3-GuK reveals that PDZ and SH3-GuK form a structural and functional supramodule. Conclusion: Formation of the PDZ-SH3-GuK supramodule may be a common feature of MAGUK scaffold proteins. Significance: These findings can guide future functional studies of MAGUKs.