Protein-Protein Interaction

Protein-protein interactions (PPIs) are biological interactions, essential for almost every process going on within a cell. So, in order to understand the physiology of the cell in normal and diseased state, it is crucial to study the protein-protein interactions taking place within the cells. Since drugs can affect such interactions, the understanding of such interactions is significantly crucial for drug development processes.

Protein-protein interaction networks (PPINs) are mathematical representations of the physical contacts among various proteins within the cells. These physical contacts are usually very specific for the type of cell and protein as well, take place between defined binding regions in the proteins, and serve for a particular biological function. The following image represents how various proteins from different protein families are interacting with each other in order to create a complex molecular biology network to perform their respective functions:

The totality of protein-protein interactions taking place within a cell, organism, or a specific biological context, is known as Interactome.

Protein-Protein Interaction Assays

The protein-protein interaction assays can be broadly classified into three main categories:

  1. In Vitro - this method requires the whole procedure completed outside the cell in a controlled environment in a laboratory, i.e., affinity chromatography, tandem affinity purification, protein fragment complementation, x-ray crystallography, NMR, phage display, spectroscopy and protein assays.

  2. In Vivo - these techniques apply the whole procedure on the living cell or the organism itself.

  3. In Silico - techniques that can be performed by using computer and computer simulations - these include sequence and structure based approaches, in-silico two hybrid approaches, gene expression-based approaches, chromosome proximity and gene fusion techniques, phylogenetic profiling and tree building techniques, etc.

Importance of Protein-Protein Interactions

In a living cell to perform their biological functions, proteins rarely act as isolated species rather more than 80% of the proteins perform their functions in groups. The function of an unidentified protein can be predicted by its interactions with a protein of known function. The thorough study of PPIs is also important to demonstrate the molecular mechanism of cellular processes of proteins.

The understanding of PPIs can be used to characterize the relationships between proteins that form multi-molecular complexes such as the proteasome. It assigns putative to uncharacterized proteins and adds fine-grained details about the steps within the signaling pathway.

Properties of PPIs

Following are momentous properties of PPIs are:

  • The kinetic properties of the enzymes can be modified by PPIs.

  • PPIs can allow substrate channeling.

  • They can create a new binding site for the small molecules.

  • They can suppress or activate a protein.

  • PPIs can perform regulatory roles in downstream or upstream regulation of the protein.

  • They can also alter the specificity of binding of the protein for its particular substrate by changing its interactions.

Transient & Stable Interactions

Protein-protein interactions can provide both the transient and stable interactions:

  • Transient interactions - brief interactions modifying and carrying a protein leading to further change, e.g., protein kinases, nuclear pore importins, etc. such interactions constitute the most dynamic part of interactome.

  • Stable interactions - interactions taking place within protein complexes, e.g., ribosomes, hemoglobin, etc.

Databases for the in-silico Analysis of Protein-Protein Interactions

The databases utilized for predicting and analyzing the protein-protein interactions include:

  • STRING - the most commonly utilized database for PPIs analysis. It provides the information about the known and predicted protein-protein interactions. The interactions include direct (physical) and indirect (functional) associations; they are based on computational prediction, knowledge transfer between organisms, and interactions aggregated from other (primary) databases.

  • BioGrid - a repository of various protein-protein interactions with data compiled through comprehensive curation efforts.

  • BIND/BOND - a collection of records documenting molecular interactions, including high-throughput data submissions and hand-curated information gathered from the scientific literature.

  • DIP/LiveDIP - Database of Interacting Proteins - catalogs experimentally determined interactions between proteins. It integrates information from various sources and creates a single, consistent set of protein-protein interactions. The data stored within the DIP database were curated, both, manually by expert curators and also automatically using computational approaches that utilize the knowledge about the protein-protein interaction networks extracted from the most reliable, core subset of the DIP data.

  • HPRD - Human Protein Reference Database - a database of curated proteomic information pertaining to human proteins. All the information in HPRD has been manually extracted from the literature by expert biologists who read, interpret and analyze the published data.

  • IntAct - provides a freely available, open source database system and analysis tools for molecular interaction data. All interactions are derived from literature curation or direct user submissions and are freely available.

  • MINT - Molecular INTeraction database - focuses on experimentally verified protein-protein interactions mined from the scientific literature by expert curators. It is a database designed to store data on functional interactions between proteins. Beyond cataloguing binary complexes, MINT was conceived to store other types of functional interactions, including enzymatic modifications of one of the partners.

  • Struct2Net - provides structure-based computational predictions of protein-protein interactions (PPIs). The input to Struct2Net is either one or two amino acid sequences in FASTA format. The output gives a list of interactors if one sequence is provided and an interaction prediction if two sequences are provided.

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