PDZ domain

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 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, i. e. a PDZ binding motif.

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. 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. When studied, PDZ domains are usually isolated as monomers, however some PDZ proteins form dimers. The function of PDZ dimers as compared to monomers is not yet known.

PDZ domains have two main functions: Localizing cellular elements, and regulating cellular pathways. The first discovered function of the PDZ domains was to anchor receptor proteins in the membrane to cytoskeletal components. PDZ domains also have regulatory functions on different signaling pathways. Any protein may have one or several PDZ domains, which can be identical or unique (see figure to right). This variety allows these proteins to be very versatile in their interactions. Different PDZ domains in the same protein can have different roles, each binding a different part of the target protein or a different protein altogether.

PDZ domains play a vital role in organizing and maintaining complex scaffolding formations. PDZ domains are found in diverse proteins, but all assist in localization of cellular elements. PDZ domains are primarily involved in anchoring receptor proteins to the cytoskeleton. For cells to function properly it is important for components—proteins and other molecules— to be in the right place at the right time. Proteins with PDZ domains bind different components to ensure correct arrangements. Without such an interaction, receptors would diffuse out of the synapse due to the fluid nature of the lipid membrane. PDZ domains are also utilized to localize elements other than receptor proteins. In the human brain, nitric oxide often acts in the synapse to modify cGMP levels in response to NMDA receptor activation. In order to ensure a favorable spatial arrangements, neuronal nitric oxide synthase (nNOS) is brought close to NMDA receptors via interactions with PDZ domains on PSD 95, which concurrently binds nNOS and NMDA receptors. PDZ domains also have a regulatory role in mechanosensory signaling in proprioceptors and vestibular and auditory hair cells. The protein Whirlin (WHRN) localizes in the post synaptic neurons of hair cells that transform mechanical movement into action potentials that the body can interpret. WHRN proteins contains three PDZ domains. The domains located near the N terminus bind to receptor proteins and other signaling components. When the one of these PDZ domains is inhibited, the signaling pathways of the neurons are disrupted, resulting in auditory, visual, and vestibular impairment. This regulation is thought to be based on the physical positioning WHRN and the selectivity of its PDZ domain. Regulation of receptor proteins occurs when the PDZ domain on the EBP50 protein binds to the C terminus of the beta 2 adrenergic receptor (β2 AR). EBP50 also associates with a complex that connects to actin, thus serving as a link between the cytoskeleton and β2 AR. The β2 AR receptor is eventually endocytosed, where it will either be consigned to a lysosome for degradation or recycled back to the cell membrane. Scientists have demonstrated that when the Ser 411 residue of the β2 AR PDZ binding domain, which interacts directly with EBP50, is phosphorylated, the receptor is degraded. If Ser 411 is left unmodified, the receptor is recycled. The role played by PDZ domains and their binding sites indicate a regulative relevance beyond simply receptor protein localization. PDZ domains are being studied further to better understand the role they play in different signaling pathways. Research has increased as these domains have been linked to different diseases including cancer as discussed above.

PDZ domain function can be both inhibited and activated by various mechanisms. Two of the most prevalent include allosteric interactions and posttranslational modifications. This modification is primarily an inhibitor of PDZ domain and ligand activity. In some examples, phosphorylation of amino acid side chains eliminates the ability of the PDZ domain to form hydrogen bonds, disrupting the normal binding patterns. The end result is a loss of PDZ domain function and further signaling. Another way phosphorylation can disrupt regular PDZ domain function is by altering the charge ratio and further affecting binding and signaling. In rare cases researchers have seen post translational modifications activate PDZ domain activity but these cases are few. Another post translational modification that can regulate PDZ domains is the formation of disulfide bridges. Many PDZ domains contain cysteines and are susceptible to disulfide bond formation in oxidizing conditions. This modification acts primarily as an inhibitor of PDZ domain function.