Many proteins in cells are tagged at their tail end, or C-terminus, with a code that instructs the cell to distribute the protein to its proper location. This code, called the PDZ ligand or PL, is read and decoded by PDZ proteins that direct the distribution of the tagged protein. Arbor Vita Corporation has identified nearly all of the PDZ domains in the human proteome and has decoded most of them. The company has applied this knowledge to its discovery and development of novel diagnostics and therapeutics, including a new treatment for stroke and a rapid test for avian influenza.

Importance to human biology

PDZ proteins are named for the first letter of the first three proteins in the family to be discovered (PSD-95, DLG, and ZO-1). PDZs play a key role in cellular signaling, initiating and regulating the assembly of proteins including membrane proteins, cytoskeletal proteins, kinases and other proteins. Interrupting the interaction of PDZ proteins with their protein ligand (PL) binding partners may present a novel opportunity to control multiple signaling cascades in complex diseases, offering the potential for the development of stroke and cardiac therapeutics, and treatments for cancer, Alzheimer's disease, Parkinson's disease and inflammation among others.

Role in cell signaling

The structural features of PDZ domains allow them to mediate specific protein-protein interactions that underlie the assembly of large protein complexes involved in signaling or subcellular transport. PDZ domain-containing proteins play central roles in organizing signal transduction complexes, clustering membrane receptors and maintaining cell polarities. The PDZ protein-protein interaction is targetable because this interaction occurs in a protein pocket, formed by the PDZ domain. By targeting specific PDZ protein interactions, the specific functions of the signaling pathways are targeted, allowing development of therapeutics that have a narrow focus. In addition, AVC has isolated all known PDZ domains in the human genome and developed a platform that allows early-stage development of drugs that are selective for the PDZ domain of interest, allowing a significant increase in successful development at reduced time and cost.