PDZ Domain-Peptide Interaction Prediction

Table of Contents

Background

The human genome contains approximately 26,000 protein-coding genes, which through alternative splicing can direct the synthesis of thousands of different proteins. The majority of these proteins interact with other proteins to coordinate a variety of cellular processes including DNA replication, cell cycle control, and signal transduction. The ability to accurately detect these interactions enables the assembly of protein interaction networks which can be used to better understand and study the biochemistry of the cell.

Computational PPI Prediction

Several computational methods to predict protein protein interactions (PPIs) have been developed and can be used to support or prioritize experiments. Such methods fall into a range of categories from physics to statistics-based method, however they all face several challenges. For physics-based prediction methods, the structures of the proteins are often unavailable or protein flexibility is not taken into consideration. Sequence based methods like PWMs can only represent short binding motifs and often do not account for interdependencies between residues and positions. In general, the computational prediction of PPIs is considered an extremely difficult problem that is not fully addressed by any existing method.

Many PPIs are mediated by peptide recognition domains (PRDs), which are evolutionary conserved modular interaction domains often found combined in different ways to form larger proteins. Proteins containing PRDs are used by the cell for numerous processes such as the co-localization of proteins, regulation of signaling processes or recognition of protein post-translational modifications. Interactions usually occur through the recognition of short linear sequences in the target protein such as proline-rich or C terminal motifs. Because of their simpler binding sites and straightforward modes of target recognition, it is easier to computationally predict peptide-PRD interactions than it is to predict PPIs more generally.

Computational Prediction of PDZ Domain Interactions

The PSD95/DlgA/Zo-1 (PDZ) domain is an ideal model for studying the computational prediction of peptide-PRD interactions since they are have important biological roles, are well studied and one of the simplest binding sites among PRDs. PDZ domains are found in bacteria, yeast, plants, and metazoans with 250 found in humans. They often interact with ion channels, adhesion molecules, and neurotransmitter receptors in signaling and scaffolding proteins. The biological roles include maintaining cell polarity, facilitating signal coupling, and regulating synaptic development. Their importance is emphasized, as mutations of the PDZ domain in different proteins have been associated with various diseases.

Sequence Based Prediction

Recently, two high through put experiments have been performed to study different PDZ domains. This has enabled the development of computational predictors of PDZ domain interactions. This project focuses on using a machine learning method called support vector machines to computationally predict PDZ domain interactions directly from a given proteome. [Read More]

Structure Based Prediction

While the previously developed sequence based predictor is able to more accurately and precisely scan proteomes of different organisms for PDZ domain binders, its performance relies on the sequence similarity between testing and training domains. On the other hand, it is known that the domain structure can play a big role in determining PDZ domain binding specificity. Therefore, we developed a structure based predictor of PDZ domain peptide interactions which is trained using PDZ domain structure features. [Read More]

POW! PDZ Domain-Peptide Interaction Prediction

The sequence-based and structure-based predictors are now available via a website called POW! and support the majority of human, mouse, fly and worm PDZ domains.

POW! Website: http://webservice.baderlab.org/domains/POW/

A simple command line user interface that allows users to run POW! locally on their computer is also available. It is written in Java and can be downloaded below. Please unzip the file below and consult the Readme for more details.

POW! CLUI: POWCLUI.zip

Team

• Shirley Hui
• Gary Bader

CategoryProject