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.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.Membrane-associated guanylate kinases (MAGUKs) 4 were originally referred to as a group of cell junction proteins composed of synaptic scaffold protein PSD-95 from mammals, Dlg tumor suppressor from Drosophila, and tight junction protein ZO-1 from mammalian epithelia (1). MAGUKs are now known as a large family of scaffold proteins that play critical roles in diverse cellular processes including intercellular connections, cell polarity development and maintenance, neuronal plasticity, and cell survival in both metazoan and premetazoan (2-4). Despite the large differences in their lengths and amino acid sequences, every member of the MAGUK family of proteins except for membrane associated guanylate kinase inverted (MAGI) shares a core structural module composed of a PSD-95/Dlg/ZO-1 (PDZ) domain, an Src homology 3 (SH3) domain, and a catalytically inactive guanylate kinase (GuK) domain arranged sequentially into a PDZ-SH3-GuK tandem (see Fig. 1A). Recent studies have demonstrated that functional interaction between Dlg SH3-GuK tandem and its partner GuKHolder is dependent on the presence of the upstream PDZ domain of Dlg and that this interaction is further regulated by the PDZ domain binding peptide (5, 6). Considering the highly conserved domain organization feature of MAGUKs throughout evolution, we hypothesized that the signature PDZ-SH3-GuK tandem of MAGUKs may form a structural supramodule with three domains interacting with each other to assemble into an integral structural unit, which has functions distinct from those of the isolated doma...

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NF-erythroid 2–related factor 2 (Nrf2) is a major transcription factor to protect cells against reactive oxygen species (ROS) and reactive toxicants. Meanwhile, Nrf2 can inhibit contact dermatitis through redox-dependent and -independent pathways. However, the underlying mechanisms of how Nrf2 mediates irritant contact dermatitis (ICD) are still unclear. In this article, we elucidated the role of Nrf2 in 12-O-tetradecanoylphorbol-13-acetate (TPA)-induced acute ICD. Our study demonstrated that the ear thickness, redness, swelling, and neutrophil infiltration were significantly increased, accompanied by increased expression of inflammatory cytokines (IL-1α, IL-1β, IL-6, etc.) and decreased expression of antioxidant genes (HO-1 and NQO1) in Nrf2 knockout mice. Moreover, ERK phosphorylation was elevated in mouse embryonic fibroblasts (MEFs) from Nrf2 knockout mouse. Inhibition of ERK significantly alleviated TPA-induced cutaneous inflammation and ROS accumulation in MEFs derived from mouse. Conversely, ROS scavenging inhibited the ERK activation and TPA-induced inflammation in MEFs. Taken together, the findings illustrate the key role of the Nrf2/ROS/ERK signaling pathway in TPA-induced acute ICD.