Protein-protein interaction
Encyclopedia
Protein–protein interactions occur when two or more protein
s bind together, often to carry out their biological function
. Many of the most important molecular processes in the cell such as DNA replication
are carried out by large molecular machines that are built from a large number of protein components organised by their protein–protein interactions. Protein interactions have been studied from the perspectives of biochemistry
, quantum chemistry
, molecular dynamics
, chemical biology
, signal transduction
and other metabolic or genetic/epigenetic networks
. Indeed, protein–protein interactions are at the core of the entire interactomics
system of any living cell.
Interactions between proteins are important for the majority of biological functions. For example, signals from the exterior of a cell
are mediated to the inside of that cell by protein–protein interactions of the signaling molecules. This process, called signal transduction
, plays a fundamental role in many biological processes and in many diseases (e.g. cancer
s). Proteins might interact for a long time to form part of a protein complex
, a protein may be carrying another protein (for example, from cytoplasm
to nucleus
or vice versa in the case of the nuclear pore
importins), or a protein may interact briefly with another protein just to modify it (for example, a protein kinase
will add a phosphate to a target protein). This modification of proteins can itself change protein–protein interactions. For example, some proteins with SH2 domain
s only bind to other proteins when they are phosphorylated on the amino acid
tyrosine while bromodomain
s specifically recognise acetylated lysines. In conclusion, protein–protein interactions are of central importance for virtually every process in a living cell. Information about these interactions improves our understanding of diseases and can provide the basis for new therapeutic approaches.
of the method. A high sensitivity means that many of the interactions that occur in reality are detected by the screen. A high specificity indicates that most of the interactions detected by the screen are also occurring in reality. Methods such as yeast two-hybrid screening can be used to detect novel protein–protein interactions. There are also many biophysical methods for investigating the nature and properties of interactions. At the theoretical level, large scale experimental data on interactions is often modelled by graph theoretic methods.
techniques. Although protein interaction diagrams are common in textbooks, diagrams of whole cell protein interaction networks were not as common since the level of complexity made them difficult to generate. One example of a manually produced molecular interaction map is Kurt Kohn's 1999 map of cell cycle control.
Drawing on Kohn's map, in 2000 Schwikowski, Uetz, and Fields published a paper on protein–protein interactions in yeast, linking together 1,548 interacting proteins determined by two-hybrid testing. They used a layered graph drawing
method to find an initial placement of the nodes and then improved the layout using a force-based algorithm.
The Cytoscape
software is a widely used application to visualise protein-protein interaction networks.
s that allow the interactions to be assembled and studied further. The first of these databases was DIP, the database of interacting proteins
. Since that time a large number of further database collections have been created such as BioGRID
and STRING
.
Protein
Proteins are biochemical compounds consisting of one or more polypeptides typically folded into a globular or fibrous form, facilitating a biological function. A polypeptide is a single linear polymer chain of amino acids bonded together by peptide bonds between the carboxyl and amino groups of...
s bind together, often to carry out their biological function
Function (biology)
A function is part of an answer to a question about why some object or process occurred in a system that evolved through a process of selection. Thus, function refers forward from the object or process, along some chain of causation, to the goal or success...
. Many of the most important molecular processes in the cell such as DNA replication
DNA replication
DNA replication is a biological process that occurs in all living organisms and copies their DNA; it is the basis for biological inheritance. The process starts with one double-stranded DNA molecule and produces two identical copies of the molecule...
are carried out by large molecular machines that are built from a large number of protein components organised by their protein–protein interactions. Protein interactions have been studied from the perspectives of biochemistry
Biochemistry
Biochemistry, sometimes called biological chemistry, is the study of chemical processes in living organisms, including, but not limited to, living matter. Biochemistry governs all living organisms and living processes...
, quantum chemistry
Quantum chemistry
Quantum chemistry is a branch of chemistry whose primary focus is the application of quantum mechanics in physical models and experiments of chemical systems...
, molecular dynamics
Molecular dynamics
Molecular dynamics is a computer simulation of physical movements of atoms and molecules. The atoms and molecules are allowed to interact for a period of time, giving a view of the motion of the atoms...
, chemical biology
Chemical biology
Chemical biology is a scientific discipline spanning the fields of chemistry and biology that involves the application of chemical techniques and tools, often compounds produced through synthetic chemistry, to the study and manipulation of biological systems. This is a subtle difference from...
, signal transduction
Signal transduction
Signal transduction occurs when an extracellular signaling molecule activates a cell surface receptor. In turn, this receptor alters intracellular molecules creating a response...
and other metabolic or genetic/epigenetic networks
Graph theory
In mathematics and computer science, graph theory is the study of graphs, mathematical structures used to model pairwise relations between objects from a certain collection. A "graph" in this context refers to a collection of vertices or 'nodes' and a collection of edges that connect pairs of...
. Indeed, protein–protein interactions are at the core of the entire interactomics
Interactomics
Interactomics is a discipline at the intersection of bioinformatics and biology that deals with studying both the interactions and the consequences of those interactions between and among proteins, and other molecules within a cell. The network of all such interactions is called the Interactome...
system of any living cell.
Interactions between proteins are important for the majority of biological functions. For example, signals from the exterior of a cell
Cell (biology)
The cell is the basic structural and functional unit of all known living organisms. It is the smallest unit of life that is classified as a living thing, and is often called the building block of life. The Alberts text discusses how the "cellular building blocks" move to shape developing embryos....
are mediated to the inside of that cell by protein–protein interactions of the signaling molecules. This process, called signal transduction
Signal transduction
Signal transduction occurs when an extracellular signaling molecule activates a cell surface receptor. In turn, this receptor alters intracellular molecules creating a response...
, plays a fundamental role in many biological processes and in many diseases (e.g. cancer
Cancer
Cancer , known medically as a malignant neoplasm, is a large group of different diseases, all involving unregulated cell growth. In cancer, cells divide and grow uncontrollably, forming malignant tumors, and invade nearby parts of the body. The cancer may also spread to more distant parts of the...
s). Proteins might interact for a long time to form part of a protein complex
Protein complex
A multiprotein complex is a group of two or more associated polypeptide chains. If the different polypeptide chains contain different protein domain, the resulting multiprotein complex can have multiple catalytic functions...
, a protein may be carrying another protein (for example, from cytoplasm
Cytoplasm
The cytoplasm is a small gel-like substance residing between the cell membrane holding all the cell's internal sub-structures , except for the nucleus. All the contents of the cells of prokaryote organisms are contained within the cytoplasm...
to nucleus
Cell nucleus
In cell biology, the nucleus is a membrane-enclosed organelle found in eukaryotic cells. It contains most of the cell's genetic material, organized as multiple long linear DNA molecules in complex with a large variety of proteins, such as histones, to form chromosomes. The genes within these...
or vice versa in the case of the nuclear pore
Nuclear pore
Nuclear pores are large protein complexes that cross the nuclear envelope, which is the double membrane surrounding the eukaryotic cell nucleus. There are about on average 2000 nuclear pore complexes in the nuclear envelope of a vertebrate cell, but it varies depending on cell type and the stage in...
importins), or a protein may interact briefly with another protein just to modify it (for example, a protein kinase
Protein kinase
A protein kinase is a kinase enzyme that modifies other proteins by chemically adding phosphate groups to them . Phosphorylation usually results in a functional change of the target protein by changing enzyme activity, cellular location, or association with other proteins...
will add a phosphate to a target protein). This modification of proteins can itself change protein–protein interactions. For example, some proteins with SH2 domain
SH2 domain
The SH2 domain is a structurally conserved protein domain contained within the Src oncoprotein and in many other intracellular signal-transducing proteins...
s only bind to other proteins when they are phosphorylated on the amino acid
Amino acid
Amino acids are molecules containing an amine group, a carboxylic acid group and a side-chain that varies between different amino acids. The key elements of an amino acid are carbon, hydrogen, oxygen, and nitrogen...
tyrosine while bromodomain
Bromodomain
A bromodomain is a protein domain that recognizes acetylated lysine residues such as those on the N-terminal tails of histones. This recognition is often a prerequisite for protein-histone association and chromatin remodeling. The domain itself adopts an all-α protein fold, a bundle of four alpha...
s specifically recognise acetylated lysines. In conclusion, protein–protein interactions are of central importance for virtually every process in a living cell. Information about these interactions improves our understanding of diseases and can provide the basis for new therapeutic approaches.
Methods to investigate protein–protein interactions
As protein–protein interactions are so important there are a multitude of methods to detect them. Each of the approaches has its own strengths and weaknesses, especially with regard to the sensitivity and specificitySensitivity and specificity
Sensitivity and specificity are statistical measures of the performance of a binary classification test, also known in statistics as classification function. Sensitivity measures the proportion of actual positives which are correctly identified as such Sensitivity and specificity are statistical...
of the method. A high sensitivity means that many of the interactions that occur in reality are detected by the screen. A high specificity indicates that most of the interactions detected by the screen are also occurring in reality. Methods such as yeast two-hybrid screening can be used to detect novel protein–protein interactions. There are also many biophysical methods for investigating the nature and properties of interactions. At the theoretical level, large scale experimental data on interactions is often modelled by graph theoretic methods.
Visualization of networks
Visualization of protein–protein interaction networks is a popular application of scientific visualizationScientific visualization
Scientific visualization is an interdisciplinary branch of science according to Friendly "primarily concerned with the visualization of three-dimensional phenomena , where the emphasis is on realistic renderings of volumes, surfaces, illumination sources, and so forth, perhaps...
techniques. Although protein interaction diagrams are common in textbooks, diagrams of whole cell protein interaction networks were not as common since the level of complexity made them difficult to generate. One example of a manually produced molecular interaction map is Kurt Kohn's 1999 map of cell cycle control.
Drawing on Kohn's map, in 2000 Schwikowski, Uetz, and Fields published a paper on protein–protein interactions in yeast, linking together 1,548 interacting proteins determined by two-hybrid testing. They used a layered graph drawing
Layered graph drawing
Layered graph drawing is a type of graph drawing in which the vertices of a directed graph are drawn in horizontal rows or layers with the edges generally directed downwards...
method to find an initial placement of the nodes and then improved the layout using a force-based algorithm.
The Cytoscape
Cytoscape
Cytoscape is an open source bioinformatics software platform for visualizing molecular interaction networks and integrating with gene expression profiles and other state data. Additional features are available as plugins...
software is a widely used application to visualise protein-protein interaction networks.
Database collections
Methods for identifying interacting proteins have defined hundreds of thousands of interactions. These interactions are collected together in specialised biological databaseBiological database
Biological databases are libraries of life sciences information, collected from scientific experiments, published literature, high-throughput experiment technology, and computational analyses. They contain information from research areas including genomics, proteomics, metabolomics, microarray...
s that allow the interactions to be assembled and studied further. The first of these databases was DIP, the database of interacting proteins
Database of Interacting Proteins
The catalogs experimentally determined interactions between proteins. It combines information from a variety of sources to create a single, consistent set of protein–protein interactions...
. Since that time a large number of further database collections have been created such as BioGRID
BioGRID
The Biological General Repository for Interaction Datasets is a curated biological database of protein-protein and genetic interactions created in 2003 The Biological General Repository for Interaction Datasets (BioGRID) is a curated biological database of protein-protein and genetic interactions...
and STRING
STRING
In molecular biology, STRING is a database and web resource of known and predicted protein-protein interactions....
.
See also
- InteractomicsInteractomicsInteractomics is a discipline at the intersection of bioinformatics and biology that deals with studying both the interactions and the consequences of those interactions between and among proteins, and other molecules within a cell. The network of all such interactions is called the Interactome...
- Complex systems biologySystems biologySystems biology is a term used to describe a number of trends in bioscience research, and a movement which draws on those trends. Proponents describe systems biology as a biology-based inter-disciplinary study field that focuses on complex interactions in biological systems, claiming that it uses...
- Protein–protein interaction prediction
- Protein–protein interaction screening