The PDZ domain is a common structural domain of 80-90 amino-acids found in the signaling proteins of bacteria, yeast, plants, viruses and animals. Proteins containing PDZ domains play a key role in anchoring receptor proteins in the membrane to cytoskeletal components. Proteins with these domains help hold together and organize signaling complexes at cellular membranes. These domains play a key role in the formation and function of signal transduction complexes. PDZ domains also play a highly significant role in the anchoring of cell surface receptors (such as Cftr and FZD7) to the actin cytoskeleton via mediators like NHERF and ezrin. PDZ is an initialism combining the first letters of the first three proteins discovered to share the domain — post synaptic density protein (PSD95), Drosophila disc large tumor suppressor (Dlg1), and zonula occludens-1 protein (zo-1). PDZ domains have previously been referred to as DHR (Dlg homologous region) or GLGF (glycine-leucine-glycine-phenylalanine) domains. In general PDZ domains bind to a short region of the C-terminus of other specific proteins. These short regions bind to the PDZ domain by beta sheet augmentation. This means that the beta sheet in the PDZ domain is extended by the addition of a further beta strand from the tail of the binding partner protein. The C-terminal carboxylate group is bound by a nest (protein structural motif) in the PDZ domain. Origins of discovery PDZ is an acronym derived from the names of the first proteins in which the domain was observed. Post-synaptic density protein 95 (PSD-95) is a synaptic protein found only in the brain. Drosophila disc large tumor suppressor (Dlg1) and zona occludens 1 (ZO-1) both play an important role at cell junctions and in cell signaling complexes. Since the discovery of PDZ domains more than 20 years ago, hundreds of additional PDZ domains have been identified. The first published use of the phrase “PDZ domain” was not in a paper, but a letter. In September 1995, Dr. Mary B. Kennedy of the California Institute of Technology wrote a letter of correction to Trends in Biomedical Sciences. Earlier that year, another set of scientists had claimed to discover a new protein domain which they called a DHR domain. Dr. Kennedy refuted that her lab had previously described exactly the same domain as a series of “GLGF repeats”. She continued to explain that in order to “better reflect the origin and distribution of the domain,” the new