Protein-Protein Interactions

Proteins inside the cell generally exert their function in multiprotein complexes. These complexes are considered to be highly dynamic structures changing their composition over time and cell state, thus the same protein may fulfill different functions depending on its binding partners. Such interactions play a vital role in cellular processes, therefore studying networks of interacting proteins can give fundamental biological insights.

A myriad of methods have been developed and enhanced over the years for the investigation of protein–protein interactions. Proteomics based on quantitative mass spectrometry combined with affinity purification protocols has become the method of choice to map and follow the dynamic changes in protein-protein interactions – including the ones occurring during cellular signaling events.

Protein interaction networks

The structure and nature of protein interaction networks, which are pivotal to the proper functioning of the basic molecular mechanisms underlying cellular life, is best appreciated in biological networks as a part of complex system biology, particularly due to the rich datasets of protein interactions available for study.

Protein interaction networks can elucidate the molecular basis of diseases, which in turn can provide us with better methods for their prevention, diagnosis and treatment. A thorough analysis of such networks can also aid in assessing the drug ability of molecular targets from network topology, delineating frequent interaction network motifs, drawing comparisons between model organisms and human, and also estimating interactions reliability.

Protein interaction networks can be created using protein interactions determined by any single or a combination of multiple experimental methods and data sets, where each protein is represented by a node, and two proteins are linked with each other if they have been shown to interact.

Methods to study protein-protein interactions

The yeast two-hybrid system (originally published in 1989) permits the profiling of protein interactions of any two proteins, which may be scaled up to cover the whole proteome of an organism. This technique has been successfully applied to screen for protein-protein interactions of different eukaryotic species such as Saccharomyces cerevisiae, Caenorhabditis elegans, Drosophila melanogaster, as well as for a partial human interactome.

Affinity purification-mass spectrometry (APMS) is based on the biochemical purification of proteins from cell extracts. After purification, the proteins that are bound (preys) to the protein purified (bait) are determined using mass spectrometry. This strategy is employed to identify protein interactions under the physiological conditions within a cell.

For the identification of weak and ephemeral protein interactions, which are lost during the washing steps in normal purification protocols, chemical cross-linking approaches have been developed. Through reversible cross-linking, even weakly interacting proteins become strongly associated with the bait or the protein complex purified by the formation of covalent bonds and can be biochemically purified.

A paramount challenge in analyzing the large data sets is in the distinction of true protein interactions from the experimental noise that exists in the raw data obtained by a large-scale screening method. This requires robust methods for the calculation of confidence scores for protein-protein interactions.


  4. Mishra NC. Introduction to Proteomics: Principles and Applications. John Wiley & Sons, 2011; pp. 115-136.

Further Reading

Last Updated: Jul 24, 2023

Dr. Tomislav Meštrović

Written by

Dr. Tomislav Meštrović

Dr. Tomislav Meštrović is a medical doctor (MD) with a Ph.D. in biomedical and health sciences, specialist in the field of clinical microbiology, and an Assistant Professor at Croatia's youngest university - University North. In addition to his interest in clinical, research and lecturing activities, his immense passion for medical writing and scientific communication goes back to his student days. He enjoys contributing back to the community. In his spare time, Tomislav is a movie buff and an avid traveler.


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