319

20.5

Systems Biology Helps to Discover the Causes of Disease

Response Comments to Questions 5.1 to 5.5

Task 5.1: Answers B-E are correct

Protein–protein interactions (PPI) play an important role in the organism. One example is

signaling cascades, in which different proteins interact with each other (e.g. activate one

after the other) and regulate or typically amplify cellular signals. In addition to pairwise

interactions (number of possible interactions [n² − n]/2), there are of course also com­

plexes (number of possible complexes is 2ⁿ) between proteins, so there are a large number

of possible PPIs, making it difficult to detect all interaction partners experimentally. In

some cases, there are also tissue-specific interactions. Here, it can be quite useful to focus

on only a few interesting interactions, such as tissue- or disease-specific, where interaction

databases are helpful. The STRING database is an interaction database and contains

numerous experimentally determined and bioinformatically predicted protein interactions.

Thus, individual interaction partners can be found very well, e.g. to perform network anal­

yses or to better evaluate microarray experiments, but also to obtain orthologous genes

(search for Cluster of Orthologous Groups, COG, included). The KEGG database contains

network maps for important signalling pathways, e.g. Wnt, MAPK, Ras-Raf-Mek-Erk

signalling pathway, apoptosis or the cell cycle, but also provides a lot of additional infor­

mation, e.g. on metabolism, enzymes and diseases. Thus, one can find entire signaling

pathways (e.g. for a disease) and thus, for example, identify metabolic pathways involved

or find drug targets. The PlateletWeb database (own chair database) contains protein inter­

actions primarily for the platelet, but also for other human cells, such as phosphorylations.

The listed interactions in PlateletWeb are based on experimental data sets, e.g. proteomics

data. The databases iHOP (information hyperlinked over proteins) and HPRD (Human

Protein Reference Database) also contain experimentally determined protein interactions

and numerous related information. However, there are many other databases, such as

IntAct (https://www.ebi.ac.uk/intact), MINT (https://mint.bio.uniroma2.it/mint), and

BioGRID (https://www.thebiogrid.org). In all these databases you can find numerous

interactions with which you can then build a network. However, it is always advisable to

use several databases and compare them with each other in order to find common and

trustworthy interactions.

A protein–protein interaction network can be constructed using the following steps: i)

network reconstruction and ii) network analysis. i) Network reconstruction can be done

using different databases, e.g. protein–protein interactions from the STRING database.

This network can be saved as .sif (simple interaction file) to be read into Cytoscape. ii)

Network analysis can be done e.g. with the software Cytoscape (please have a look at

www.cytoscape.org for a short description of Cytoscape). For this purpose Cytoscape has

numerous plugins to choose from, e.g. BiNGO (biological process analysis),

AllegroMCODE (analysis of functional modules and complexes) and NetworkAnalyzer

20.5  Systems Biology Helps to Discover the Causes of Disease