Interactome

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Part of the DISC1 interactome with genes represented by text in boxes and interactions noted by lines between the genes. From Hennah and Porteous, 2009.[1]

In molecular biology, an interactome is the whole set of molecular interactions in a particular cell. The term specifically refers to physical interactions among molecules but can also mean indirect interactions among genes, i.e. genetic interactions. Mathematically, interactomes are generally displayed as graphs.

The word "interactome" was originally coined in 1999 by a group of French scientists headed by Bernard Jacq.[2] Though interactomes may be described as biological networks, they should not be confused with other networks such as neural networks or food webs.

Molecular interaction networks[edit]

Molecular interactions can occur between molecules belonging to different biochemical families (proteins, nucleic acids, lipids, carbohydrates, etc.) and also within a given family. Whenever such molecules are connected by physical interactions, they form molecular interaction networks that are generally classified by the nature of the compounds involved. Most commonly, interactome refers to protein–protein interaction (PPI) network (PIN) or subsets thereof. For instance, the Sirt-1 protein interactome and Sirt family second order interactome [3][4] is the network involving Sirt-1 and its directly interacting proteins where as second order interactome illustrates interactions up to second order of neighbors (Neighbors of neighbors). Another extensively studied type of interactome is the protein–DNA interactome, also called a gene-regulatory network, a network formed by transcription factors, chromatin regulatory proteins, and their target genes. Even metabolic networks can be considered as molecular interaction networks: metabolites, i.e. chemical compounds in a cell, are converted into each other by enzymes, which have to bind their substrates physically.

In fact, all interactome types are interconnected. For instance, protein interactomes contain many enzymes which in turn form biochemical networks. Similarly, gene regulatory networks overlap substantially with protein interaction networks and signaling networks.

Size of interactomes[edit]

Estimates of the yeast protein interactome. From[5]

It has been suggested that the size of an organism's interactome correlates better than genome size with the biological complexity of the organism.[6] Although protein–protein interaction maps containing several thousands of binary interactions are now available for several organisms, none of them is presently complete and the size of interactomes is still a matter of debate.

Yeast[edit]

The yeast interactome, i.e. all protein-protein interactions among yeast proteins, has been estimated to contain between 10,000 and 30,000 interactions. A reasonable estimate may be on the order of 20,000 interactions. Larger estimates often include indirect or predicted interactions, often from affinity purification/mass spectrometry (AP/MS) studies.

Genetic interaction networks[edit]

Genes interact in the sense that they affect each other's function. For instance, a mutation may be harmless, but when it is combined with another mutation, the combination may turn out to be lethal. Such genes are said to "interact genetically". Genes that are connected in such a way form genetic interaction networks. Some of the goals of these networks are: develop a functional map of a cell's processes, drug target identification, and to predict the function of uncharacterized genes.

In 2010, the most "complete" gene interactome produced to date was compiled from about 5.4 million two-gene comparisons to describe "the interaction profiles for ~75% of all genes in the Budding yeast," with ~170,000 gene interactions. The genes were grouped based on similar function so as to build a functional map of the cell's processes. Using this method the study was able to predict known gene functions better than any other genome-scale data set as well as adding functional information for genes that hadn't been previously described. From this model genetic interactions can be observed at multiple scales which will assist in the study of concepts such as gene conservation. Some of the observations made from this study are that there were twice as many negative as positive interactions, negative interactions were more informative than positive interactions, and genes with more connections were more likely to result in lethality when disrupted.[7]

Although extremely important and useful, the interactome is still being developed and is not complete (as of October 2010[citation needed]). There are various factors that have a role in protein interactions that have yet to be incorporated in the interactome. Many[who?] have termed the interactome as a whole as being fuzzy. The binding strength of the various proteins, microenvironmental factors, sensitivity to various procedures, and the physiological state of the cell all affect protein–protein interactions, yet are not accounted for in the interactome. Although the interactome is useful in some ways, it must be analyzed knowing that these factors exist and can affect the protein interactions.[8]

Interactomics[edit]

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.[9] Interactomics thus aims to compare such networks of interactions (i.e., interactomes) between and within species in order to find how the traits of such networks are either preserved or varied.

Interactomics is an example of "top-down" systems biology, which takes an overhead, as well as overall, view of a biosystem or organism. Large sets of genome-wide and proteomic data are collected, and correlations between different molecules are inferred. From the data new hypotheses are formulated about feedbacks between these molecules. These hypotheses can then be tested by new experiments.[10]

Methods of mapping the interactome[edit]

The study of interactomes is called interactomics. The basic unit of a protein network is the protein–protein interaction (PPI). Because an interactome considers the whole cells or organisms, there is a need to collect a massive amount of information.

Experimental methods to identify PPIs[edit]

The yeast two hybrid system (Y2H) is suited to explore the binary interactions among two proteins at a time. Affinity purification and subsequent mass spectrometry is suited to identify a protein complex. Both methods can be used in a high-throughput (HTP) fashion. Yeast two hybrid screens allow include false positive interactions between proteins that are never expressed in the same time and place; affinity capture mass spectrometry does not have this drawback, and is the current gold standard. Yeast two-hybrid data better indicates non-specific tendencies towards sticky interactions rather while affinity capture mass spectrometry better indicates functional in vivo protein-protein interactions.[11]

Predicting PPIs[edit]

Using experimental data as a starting point, homology transfer is one way to predict interactomes. Here, PPIs from one organism are used to predict interactions among homologous proteins in another organism. Some algorithms use experimental evidence on structural complexes, the atomic details of binding interfaces and produce detailed atomic models of protein-protein complexes [12][13] as well as other protein–molecule interactions.[14][15]

Text mining of PPIs[edit]

Some efforts have been made to extract systematically interaction networks directly from the scientific literature. Such approaches range in terms of complexity from simple co-occurrence statistics of entities that are mentioned together in the same context (e.g. sentence) to sophisticated natural language processing and machine learning methods for detecting interaction relationships.[16]

Studied interactomes[edit]

Viral interactomes[edit]

Viral protein interactomes consist of interactions among viral or phage proteins. They were among the first interactome projects as their genomes are small and all proteins can be analyzed with limited resources. Viral interactomes are connected to their host interactomes, forming virus-host interaction networks.[17] Some published virus interactomes include

The lambda and VZV interactomes are not only relevant for the biology of these viruses but also for technical reasons: they were the first interactomes that were mapped with multiple Y2H vectors, proving an improved strategy to investigate interactomes more completely than previous attempts have shown.

Bacterial interactomes[edit]

Relatively few bacteria have been comprehensively studied for their protein-protein interactions. However, none of these interactomes are complete in the sense that they captured all interactions. In fact, it has been estimated that none of them covers more than 20% or 30% of all interactions, primarily because most of these studies have only employed a single method, all of which discover only a subset of interactions.[25] Among the published bacterial interactomes (including partial ones) are

Species proteins total interactions type reference
Helicobacter pylori 1,553 ~3,004 Y2H [26][27]
Campylobacter jejuni 1,623 11,687 Y2H [28]
Treponema pallidum 1,040 3,649 Y2H [29]
Escherichia coli 4,288 (5,993) AP/MS [30]
Escherichia coli 4,288 2,234 Y2H [31]
Mesorhizobium loti 6,752 3,121 Y2H [32]
Mycobacterium tuberculosis 3,959 >8000 B2H [33]
Mycoplasma genitalium 482 AP/MS [34]
Synechocystis sp. PCC6803 3,264 3,236 Y2H [35]
Staphylococcus aureus (MRSA) 2,656 13,219 AP/MS [36]

The E. coli and Mycoplasma interactomes have been analyzed using large-scale protein complex affinity purification and mass spectrometry (AP/MS), hence it is not easily possible to infer direct interactions. The others have used extensive Yeast two-hybrid (Y2H) screens. The Mycobacterium tuberculosis interactome has been analyzed using a bacterial two-hybrid screen (B2H).

Eukaryotic interactomes[edit]

There have been several efforts to map eukaryotic interactomes through HTP methods. As of 2006, yeast, fly, worm, and human HTP maps have been created. While no biological interactomes have been fully characterized, over 90% of proteins in Saccharomyces cerevisiae have been screened and their interactions characterized, making it the first interactome to be nearly fully specified.[37][38][39] Other species whose interactomes have been studied in some detail include Caenorhabditis elegans and Drosophila melanogaster.

Recently, the pathogen-host interactomes of Hepatitis C Virus/Human (2008),[40] Epstein Barr virus/Human (2008), Influenza virus/Human (2009)) were delineated through HTP to identify essential molecular components for pathogens and for their host's immune system.[41]

Interactome analysis[edit]

Interactome data has been analyzed in many different ways and a huge body of literature has been published on interactome analyses. Such analyses are mainly carried out using bioinformatics methods and include the following, among many others:

Validation[edit]

First, the coverage and quality of an interactome has to be evaluated. Interactomes are never complete, given the limitations of experimental methods. For instance, it has been estimated that typical Y2H screens detect only 25% or so of all interactions in an interactome.[25] The coverage of an interactome can be assessed by comparing it to benchmarks of well-known interactions that have been found and validated by independent assays.[42]

Protein function prediction[edit]

Protein interaction networks have been used to predict the function of proteins of unknown functions.[43][44] This is usually based on the assumption that uncharacterized proteins have similar functions as their interacting proteins (guilt by association). For example, YbeB, a protein of unknown function was found to interact with ribosomal proteins and later shown to be involved in translation.[45] Although such predictions may be based on single interactions, usually several interactions are found. Thus, the whole network of interactions can be used to predict protein functions, given that certain functions are usually enriched among the interactors.[43]

Perturbations and disease[edit]

The topology of an interactome makes certain predictions how a network reacts to the perturbation (e.g. removal) of nodes (proteins) or edges (interactions).[46] Similarly, mutations of genes (and thus their proteins) can cause perturbations of networks and thus disease.[47]

Network structure and topology[edit]

Interaction networks can be analyzed using the tools of graph theory. Network properties include the degree distribution, clustering coefficients, betweenness centrality, and many others. The distribution of properties among the proteins of an interactome has revealed functional modules within a network that indicate specialized subnetworks.[48] Such modules can be functional, as in a signaling pathway, or structural, as in a protein complex. In fact, it is a formidable task to identify protein complexes in an interactome, given that a network on its own does not directly reveal the presence of a stable complex.

Network properties of interactomes[edit]

Protein interaction networks can be analyzed with the same tool as other networks. In fact, they share many properties with biological or social networks. Some of the main characteristics are as follows.

The Treponema pallidum protein interactome.[29]

Degree distribution[edit]

The degree distribution describes the number of proteins that have a certain number of connections. Most protein interaction networks show a scale-free (power law) degree distribution where the connectivity distribution P(k) ~ k−γ with k being the degree. This relationship can also be seen as a straight line on a log-log plot since, the above equation is equal to log(P(k)) ~ —y•log(k). One characteristic of such distributions is that there are many proteins with few interactions and few proteins that have many interactions, the latter being called "hubs".

Hubs[edit]

Highly connected nodes (proteins) are called hubs. Han et al.[49] have coined the term “party hub” for hubs whose expression is correlated with its interaction partners. Party hubs also connect proteins within functional modules such as protein complexes. In contrast, “date hubs” do not exhibit such a correlation and appear to connect different functional modules. Party hubs are found predominantly in AP/MS data sets, whereas date hubs are found predominantly in binary interactome network maps.[50] Note that the validity of the date hub/party hub distinction was disputed.[51][52] Party hubs generally consist of multi-interface proteins whereas date hubs are more frequently single-interaction interface proteins.[53] Consistent with a role for date-hubs in connecting different processes, in yeast the number of binary interactions of a given protein is correlated to the number of phenotypes observed for the corresponding mutant gene in different physiological conditions.[50]

Criticisms and concerns[edit]

Kiemer and Cesareni[9] raise the following concerns with the state (circa 2007) of the field:

  • The experimental procedures associated with the field are error prone leading to "noisy results". This leads to 30% of all reported interactions being artifacts. In fact, two groups using the same techniques on the same organism found less than 30% interactions in common. However, some authors have argued that such non-reproducibility results from the extraordinary sensity of various methods to small experimental variation. For instance, identical conditions in Y2H assays result in very different interactions when different Y2H vectors are used.[25]
  • Techniques may be biased, i.e. the technique determines which interactions are found.
  • Interactomes are not nearly complete with perhaps the exception of S. cerevisiae.
  • While genomes are stable, interactomes may vary between tissues, cell types, and developmental stages.
  • Genomics compares amino acids, and nucleotides which are in a sense unchangeable, but interactomics compares proteins and other molecules which are subject to mutation and evolution.
  • It is difficult to match evolutionarily related proteins in distantly related species.

See also[edit]

References[edit]

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Further reading[edit]

External links[edit]

Interactome web servers[edit]

Interactome visualization tools[edit]

Interactome databases[edit]