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What properties characterize the hub proteins of the protein-protein interaction network of Saccharomyces cerevisiae? - PubMed

What properties characterize the hub proteins of the protein-protein interaction network of Saccharomyces cerevisiae?

Diana Ekman et al. Genome Biol. 2006.

Abstract

Background: Most proteins interact with only a few other proteins while a small number of proteins (hubs) have many interaction partners. Hub proteins and non-hub proteins differ in several respects; however, understanding is not complete about what properties characterize the hubs and set them apart from proteins of low connectivity. Therefore, we have investigated what differentiates hubs from non-hubs and static hubs (party hubs) from dynamic hubs (date hubs) in the protein-protein interaction network of Saccharomyces cerevisiae.

Results: The many interactions of hub proteins can only partly be explained by bindings to similar proteins or domains. It is evident that domain repeats, which are associated with binding, are enriched in hubs. Moreover, there is an over representation of multi-domain proteins and long proteins among the hubs. In addition, there are clear differences between party hubs and date hubs. Fewer of the party hubs contain long disordered regions compared to date hubs, indicating that these regions are important for flexible binding but less so for static interactions. Furthermore, party hubs interact to a large extent with each other, supporting the idea of party hubs as the cores of highly clustered functional modules. In addition, hub proteins, and in particular party hubs, are more often ancient. Finally, the more recent paralogs of party hubs are underrepresented.

Conclusion: Our results indicate that multiple and repeated domains are enriched in hub proteins and, further, that long disordered regions, which are common in date hubs, are particularly important for flexible binding.

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Figures

Figure 1
Figure 1

Co-expression in FYI and DIP. Average PCCs of the co-expressions of party hubs (PHs) and date hubs (DHs) and their interaction partners were calculated for the FYI-defined PH and DH. Average PCCs calculated for the interaction partners in the FYI network (x axis) correlate (CC = 0.8) with the average PCCs calculated within the DIP network (y axis). The values in the DIP network are on average lower.

Figure 2
Figure 2

Hub assignment. The overlap between date hubs (DHs) and party hubs (PHs) in the two data sets; DIP and FYI. In FYI there are 108 PHs and 91 DHs (middle circle), of which 23 DHs and 20 PHs have connectivities below the hub threshold (k < 8) in DIP. Most of the FYI PHs (66) were confirmed as PHs in the DIP set, while 22 fell below the PCC cutoff (see Materials and methods). Furthermore, while most of the FYI DHs retained their DH status using DIP, a small fraction of the FYI DHs (6) were classified as PHs. Finally, 234 and 129 previously unclassified hubs were assigned as DHs and PHs in DIP.

Figure 3
Figure 3

Functional classification of party hubs, date hubs and non-hubs. The functional classification was performed using KOG [19]. This classification consists of four main functional groups: metabolism; information storage and processing; cellular processes and signaling; and poorly characterized. Unnamed proteins have been excluded, although this is fairly common among the non-hub proteins.

Figure 4
Figure 4

Protein age. The age of a protein is here estimated from the age of its domains. Domains may be found in: eukaryotes and prokaryotes (Ancient); eukaryotes (Euk); or yeast. Domains and proteins that lack homologs are called orphan domains (ODs) and orphan proteins (OPs). The age of a single domain protein is equal to the age of its composing domain, whereas each domain family represented in a multi-domain protein contributes equally to its age classification. Furthermore, each protein contributes equally to the age of its connectivity group. Hence, a two-domain protein may be half ancient and half eukaryotic. The figure shows fractions of proteins, that is, party hubs (PHs), date hubs (DHs) and non-hubs (NHs) in each age class in DIP and FYI.

Figure 5
Figure 5

Paralogs. Fraction of proteins, that is, party hubs (PHs), date hubs (DHs) and non-hubs (NHs), that have paralogs, inparalogs (i.e. paralogs that have been duplicated after the split between S. cerevisiae and S. pombe) and ohnologs (paralogs resulting from the whole genome duplication). In DIP, the fraction of party hub inparalogs is small, approximately 0.2 compared to approximately 0.4 for the other connectivity groups (P value <10-5), and so is the fraction of ohnologs for party hubs compared to the other groups (P value <10-5). The results in the FYI data set are similar, although the fraction of date hub paralogs is smaller than in the DIP data set.

Figure 6
Figure 6

Repeating domains and disorder. Results are shown for party hubs (PHs), date hubs (DHs) and non-hubs (NHs). Repeating domains in (a) DIP and (b) FYI. A domain repeat is defined as two or more adjacent domains from the same family. Fractions of proteins with domain repeats containing 2, 3, 4, 5 or 6 or more domains are displayed. Fractions of proteins in (c) DIP and (d) FYI with disordered regions of lengths 40 to 79 residues and 80 or more residues are shown. Although 40 residues is a common cut-off for disordered regions, it is somewhat arbitrary and, therefore, 80 residues was added as an alternative cut-off.

Figure 7
Figure 7

Interaction partners for party hubs (PHs) and date hubs (DHs). The displayed values are normalized fractions of the interactions (Normalized Interactions) that involve party hubs, date hubs or non-hubs for PH and DH, respectively. The values are normalized against the number of interactions that involve the respective protein types in the network. Hence, Normalized Interactions >1 signify that the given interaction pair (for example, PH-PH) is overrepresented compared to other interactions with PH, which is seen both in DIP and FYI.

Figure 8
Figure 8

Neighbors of proteins of low connectivity (white nodes), party hubs (green nodes) and date hubs (yellow nodes); an example. a) Non-hub protein PGM1 (YKL127W, large node) is the metabolic enzyme phosphoglucomutase, which consists of four well characterized domains associated with phosphoglucomutase activity. PGM1 is only connected to two other proteins, which are not hubs. b) Party hub protein CDC16 (YKL022C, large node) is an essential protein and is part of the anaphase-promoting complex (APC). It contains six tetratricopeptide domains, one additional Pfam-A domain, two Pfam-B domains and three orphan domains (blue rectangles). CDC16 interacts with party hubs, date hubs as well as two IC and NH proteins. c) Date hub protein NUP1 (YOR098C, large node) is a nuclear pore complex protein of diverse function which contains three Pfam-B domains, two orphan domains and one long disordered region (dashed). It interacts with other date hubs, party hubs and several non hub proteins. The network figures were drawn using BioLayout[52].

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