Class I PDZ-domain proteins (Class I PDZ)

Class I PDZ-domain proteins are a diverse group of scaffolding molecules defined by the presence of one or more PDZ domains that specifically recognize C-terminal peptide motifs with the consensus sequence Ser/Thr-X-Φ, where Φ represents a hydrophobic residue [1, 2]. These proteins are essential for the spatial organization of signaling pathways, as they facilitate the assembly of multi-protein complexes at specific subcellular locations, such as the postsynaptic density in neurons or tight junctions in epithelial cells [1, 3]. By anchoring receptors, ion channels, and enzymes to the cytoskeleton, Class I PDZ proteins regulate signal transduction efficiency and maintain cellular architecture and polarity [2, 5]. In pathological contexts, these proteins are often implicated in the progression of cancer through the loss of cell polarity or the over-activation of growth signaling, and in neurological conditions like ischemic stroke, where they mediate excitotoxic signaling complexes [4, 5]. Therapeutic targeting of Class I PDZ domains primarily focuses on the development of small molecules or peptidomimetics, such as Nerinetide, which disrupt specific protein-protein interactions to prevent disease-associated signaling without affecting the global function of the protein [4].

Other names

PSD-95/DlgA/zo-1 domain proteinsGLGF domain proteinsDHR domain proteinsClass I Postsynaptic density-95/Discs large/Zonula occludens-1 domain proteins

Inhibition of protein-protein interactions by competitive binding to the PDZ domain, disrupting the assembly of signaling complexes.