They comprise ~80-90 residues folded into 6 β-strands and 2 α-helices (image), can occur in one or multiple copies, and are nearly always found in cytoplasmic proteins. The interaction between a PDZ domain and its target is usually constitutive, and the domains bind either the carboxyl-terminal sequences of proteins or internal peptide sequences. PDZ domains bind to the C-terminal 4-5 residues of their target proteins, which are frequently transmembrane receptors such as GPCRs, or ion channels. (image, image, in synapse, diagram)
The consensus binding sequence contains a hydrophobic residue, which is commonly valine or isoleucine, at the very C-terminus. Residues at the -2 and -3 positions determine specificity. PDZ domains can also heterodimerize with the PDZ domains of different proteins, potentially regulating intracellular signaling. Several PDZ domains including those of syntenin, CASK, FAP, and Tiam1 can bind to the phosphoinositide PIP2. Such PIP2-PDZ domain binding is believed to control the association of PDZ domain-containing proteins with the plasma membrane.