PDZ-containing proteins as targets in human pathologies


  • Daniela Gardiol

    1. Instituto de Biología Molecular y Celular de Rosario-CONICET, Facultad de Ciencias Bioquímicas y Farmacéuticas, Rosario, Argentina
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PDZ domains are very abundant protein interaction domains widespread in nature. A large amount of evidence has underscored the importance of the PDZ interactions in the control of intracellular pathways whose abnormal regulation may lead to the development of several pathologies. This series of minireviews covers different aspects of human PDZ-containing proteins, underlining and discussing new concepts and findings.

Most key cellular processes depend on protein–protein interactions. These interactions are fundamental for cell homeostasis and rely on specific recognition modules. Such modules allow protein binding and the formation of complexes that position the different proteins in functional networks. Of these modules, the PDZ domains represent the most abundant interaction domains encoded in the human genome, and are widespread in nature from bacteria to plants and vertebrates. The name PDZ derives from the three first proteins in which they were identified: PSD95 (postsynaptic density protein 95), DLG1 (discs large) and ZO-1 (zonula occludens protein 1). PDZ domains are composed of structured stretches of approximately 80–90 residues that recognize short conserved sequences (PBM, PDZ-binding motifs), usually located at the C-terminal region of the binding partner. Although the structural basis of the PDZ-PBM recognition has been extensively analyzed, there are still many conflicting issues regarding the selectivity or promiscuity of the binding.

The PDZ-containing proteins form a large group with many different cellular functions. To date, approximately 250 PDZ domains, distributed over more than 150 proteins, have been identified in humans. These proteins are involved in many diverse biological processes, such as cell polarity, cell–cell interactions, control of proliferation, migration and immune cell recognition. Many behave as scaffolding proteins and are found in specific locations within the cell, where they are involved in the maintenance of polarity and the assembly of signal transduction complexes, including neuronal and immunological synapses. Interestingly, some specific PDZ domains not only interact with peptide targets, but also can bind to phosphatidylinositol membrane lipids. Such interactions are probably significant for both PDZ protein localization and function.

The high evolutionary conservation of PDZ modules across different species, the recognition that many PDZ-containing proteins are targets of infectious pathogens, and the observation that their expression is altered in diverse human diseases, all emphasize the biological significance of this protein family. After years of research, much evidence highlights the importance of the PDZ interactions in the control of intracellular pathways whose abnormal regulation may lead to the development of pathologies, including several types of cancer. However, many questions and paradoxes remain about the real contribution of PDZ pathway deregulation in different diseases.

This series of minireviews covers different aspects of human PDZ proteins, highlighting and discussing new concepts and findings. In particular, many human pathogenic viruses encode proteins that interact with and perturb the functions of PDZ proteins, as a common strategy for viral replication. Banks and colleagues review the increasing number of observations concerning PDZ-containing proteins as targets of oncogenic viruses, focusing on Human Papillomavirus, and considering how these interactions contribute to the development of cervical cancer.

Although a great deal of new information about the molecular structure and functions of PDZ proteins has been published in recent years, little is still known about the genetic and regulatory mechanisms that control their expression. The minireview by Facciuto and colleagues summarizes recent research on this emerging issue and discusses some controversial data about the changes in PDZ protein levels in different diseases.

Even though more than 150 PDZ proteins have been identified in humans, most of the research has been focused upon certain individual family members. The minireview by Roberts and colleagues highlights the progress made in our understanding of the biological functions of DLG1, which is one of the first and best characterized PDZ-containing proteins.

image [ Daniela Gardiol obtained her PhD at the University of Rosario, Argentina. She performed her postdoctoral training in Tumour Virology at the International Centre of Genetic Engineering and Biotechnology in Trieste, Italy, under the supervision of Dr Lawrence Banks. She is now Professor of Virology in the School of Biochemical and Pharmaceutical Sciences (University of Rosario). The current interests of her research group, at the Institute of Cellular and Molecular Biology of Rosario, are the mechanisms involved in the carcinogenesis associated with viral infections and the molecular pathways that regulate cell polarity proteins. ]