PDZ domain

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. 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 title of the domain would be changed. Thus, the name “PDZ domain” was introduced to the world. == Structure ==

PDZ domain structure is partially conserved across the various proteins that contain them. They usually have 5-6 β-strands and one short and one long α-helix. Apart from this conserved fold, the secondary structure differs across PDZ domains. 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. == Functions ==

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. Localization 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. ==Regulation of PDZ domain activity==

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. Allosteric Interactions Protein-protein interactions have been observed to alter the effectiveness of PDZ domains binding to ligands. These studies show that allosteric effects of certain proteins can affect the binding affinity for different substrates. Different PDZ domains can even have this allosteric effect on each other. This PDZ-PDZ interaction only acts as an inhibitor. Other experiments have shown that certain enzymes can enhance the binding of PDZ domains. Researchers found that the protein ezrin enhances the binding of the PDZ protein NHERF1. == PDZ proteins ==

PDZ proteins are a family of proteins that contain the PDZ domain. This sequence of amino-acids is found in many thousands of known proteins. PDZ domain proteins are widespread in eukaryotes and eubacteria, The first two PDZ domains can also interact in a similar fashion with Shaker-type K+ channels. Proteins are indicated by black lines scaled to the length of the primary sequence of the protein. Different shapes refer to different protein domains.|400x400px Glutamate receptor interacting protein (GRIP) is a post-synaptic protein that interacts with AMPA receptors in a fashion analogous to PSD-95 interactions with NMDA receptors. When researchers noticed apparent structural homology between the C-termini of AMPA receptors and NMDA receptors, they attempted to determine if a similar PDZ interaction was occurring. A yeast two-hybrid system helped them discover that out of GRIP's seven PDZ domains, two (domains four and five) were essential for binding of GRIP to the AMPA subunit called GluR2. A clinical study concluded that Fraser syndrome, an autosomal recessive syndrome that can cause severe deformations, can be caused by a simple mutation in GRIP. HOMER differs significantly from many known PDZ proteins, including GRIP and PSD-95. Instead of mediating receptors near ion channels, as is the case with GRIP and PSD-95, HOMER is involved in metabotropic glutamate signaling. Another unique aspect of HOMER is that it only contains a single PDZ domain, which mediates interactions between HOMER and type 5 metabotropic glutamate receptor (mGluR5). The single GLGF repeat on HOMER binds amino acids on the C-terminus of mGluR5. HOMER expression is measured at high levels during embryologic stages in rats, suggesting an important developmental function. Human PDZ proteins There are roughly 260 PDZ domains in humans. Several proteins contain multiple PDZ domains, so the number of unique PDZ-containing proteins is closer to 180. In the table below are some of the better studied members of this family: The table below contains all known PDZ proteins in humans (alphabetical): There is currently one known virus containing PDZ domains: == References ==