Evolution of protein complexes by duplication of homomeric interactions
© Pereira-Leal et al.; licensee BioMed Central Ltd. 2007
Received: 3 October 2006
Accepted: 5 April 2007
Published: 05 April 2007
Cellular functions are accomplished by the concerted actions of functional modules. The mechanisms driving the emergence and evolution of these modules are still unclear. Here we investigate the evolutionary origins of protein complexes, modules in physical protein-protein interaction networks.
We studied protein complexes in Saccharomyces cerevisiae, complexes of known three-dimensional structure in the Protein Data Bank and clusters of pairwise protein interactions in the networks of several organisms. We found that duplication of homomeric interactions, a large class of protein interactions, frequently results in the formation of complexes of paralogous proteins. This route is a common mechanism for the evolution of complexes and clusters of protein interactions. Our conclusions are further confirmed by theoretical modelling of network evolution. We propose reasons for why this is favourable in terms of structure and function of protein complexes.
Our study provides the first insight into the evolution of functional modularity in protein-protein interaction networks, and the origins of a large class of protein complexes.
The success of genome sequencing projects has resulted in the accumulation of catalogues of genes for hundreds of genomes. Within each genome, the genes and their proteins interact to form complex networks with properties that transcend those of individual genes. One such network is formed by the totality of physical protein-protein interactions in the cell: the protein interaction network (PIN). These networks, like many other naturally occurring networks, such as the transcriptional [1, 2] and metabolic networks , have a modular organization [4–6]. They are organized into a number of functional modules, which are sets of interacting proteins accomplishing discrete biological functions in relative spatial, temporal or chemical isolation from other modules in the network . Protein complexes are functional modules in the sense that the protein subunits of the complex are sufficient for its function, even when isolated from the system, as has been demonstrated by in vitro reconstitution of active protein complexes in a variety of studies (for example, ).
First, gene duplication and divergence is the most important force driving the expansion of eukaryotic proteomes (for example, ). Conservation of protein interactions is frequent after duplication and paralogous genes thus frequently share interaction partners . Mathematical models of network evolution based on this principle of duplication and divergence result in networks that display topological properties comparable to those of biological protein interaction networks, in particular high clustering coefficients [10, 11]. Clusters in protein networks are frequently part of protein complexes [4, 12, 13]. The clustering coefficient of a network (C) is a measure that quantifies how interconnected the proteins are , partly reflecting modularity of the network. So duplication followed by conservation of protein interactions is linked with modularity in theoretical simulations of network evolution.
Data sets investigated in this study
Pairwise interactions (%)
No. of proteins
Manual curation of small scale data (does not include yeast two hybrid data)
Compilation of small- and large-scale data
High-throughput (yeast two-hybrid)
High-throughput (yeast two-hybrid)
High-throughput tagging and mass spectometry
High-throughput tagging and mass spectometry
Three-dimensional structures of protein complexes
The third consideration is that when genes coding for proteins that form homodimers duplicate, conservation of interactions will generate dimers of paralogous proteins. In these, the stability associated with the homodimer is maintained, while at the same time asymmetry is introduced into the interaction. This asymmetry provides more degrees of evolutionary freedom and represents a source of functional novelty (discussed in ). This is illustrated by the anecdotal examples like the photosystem I (Figure 1), in which there is asymmetry in terms of the subunits bound to PsaA and PsaB, the two paralogous proteins at its core [21, 22].
These considerations suggest the following evolutionary scenario (see Figure 1), which we test in the work presented here. An initial interaction is established between two (or more) copies of the same protein (homomeric interactions; Figure 1, left). This is the stable 'seed' of a new complex, and functional and structural factors will contribute to this interaction being selected for conservation. Gene duplication and divergence with conservation of the interactions will then follow. This initially results in multiple homomeric and heteromeric complexes with different numbers of the two duplicates (Figure 1, middle), permitting functional and structural diversification. Over time, sequence divergence will produce distinct complexes with distinct functionalities. The complexes containing paralogous proteins will frequently be selected in evolution due to the advantages of asymmetry, and accretion of new interactions may follow. This evolutionary process is illustrated by the related complexes of the RecA recombinase homohexamer and the F1 ATP synthase α3:β3 hexamer (discussed below). These two functionally distinct complexes are likely to have evolved from a common homomeric ancestor .
We test the evolutionary scenario hypothesized above by investigating the following corollaries: whether duplication of genes coding for homodimers is frequently accompanied by conservation of protein interactions in protein interaction networks; whether interactions between paralogous proteins are associated with high clustering in protein interaction networks; whether these interactions are over-represented in protein complexes obtained in large-scale proteomic experiments; whether interactions between paralogous proteins are over-represented in protein complexes of known three-dimensional structure; whether these interactions are older than other interactions and, hence, paralogous dimerization precedes accretion of further interactions, as well as whether the establishment of dimers of paralogues is associated with asymmetry of protein interactions.
Duplication of homodimers with conservation of interactions
Evolutionary origin of dimers of paralogues
0.034 ± 0.006
0.134 ± 0.011
0.043 ± 0.006
0.17 ± 0.012
0.027 ± 0.001
0.062 ± 0.002
0.203 ± 0.003
0.466 ± 0.004
0.047 ± 0.004
0.091 ± 0.006
0.082 ± 0.006
0.257 ± 0.008
0.031 ± 0.003
0.033 ± 0.003
0.355 ± 0.008
0.379 ± 0.008
Duplication of homodimers and network clusters
We investigated whether duplication plays a role in determining the clustering levels of the network. The duplication and conservation scenarios in Figure 3c suggest that only duplication of proteins that form homodimers, and not other proteins, will lead to an increase in the clustering coefficient of the network. To investigate this, we implemented a theoretical model of network growth by duplication-divergence [11, 25, 26] and asked whether inclusion of self-interactions in the model increases the global clustering coefficient.
As shown in Figure 3d, the presence of self-interacting proteins increases the clustering of the network in this model. In particular, the higher the initial proportion of self-interactors, the higher the clustering of the resulting networks (see Materials and methods and Supplementary material S2 in Additional data file 1 for details of the modeling procedure). This is consistent with the result obtained in a previous theoretical study of network evolution by duplication-divergence . The increases in clustering levels in this simplified model are modest, suggesting that additional mechanisms must operate in the evolution of real networks, and that only a subset of protein complexes are derived by the mechanism proposed here.
Conversely, when we consider the four real PINs (Table 1) and ask the opposite question, whether selective removal of interactions between paralogous proteins reduces the global clustering of the network, we find that this is the case. Clustering levels are reduced by between 7% and 15% (Supplementary material S3 in Additional data file 1). This is significantly more than obtained by removal of other interactions, which has negligible effects on the global clustering of the network. These small but significant reductions are consistent with the modeling results, further supporting that this mechanism operates in the evolution of a subset of protein complexes.
This result is subject to the following caveats. First, in some cases the formation of a cluster is not due to a single multi-protein complex, but many alternative ones, which may not co-exist in time and in space. This has been described in transcription factor families [27, 28], and is illustrated in Figure 3a. Secondly, the graph representation we use for PINs is, in itself, limited; for example, it ignores the stoichiometry of the different subunits within protein complexes. For example, a protein complex composed of six identical subunits forming a ring would be depicted as a single self-interacting node, and not captured as a cluster in the PIN. Thus, although considering PINs gives us a network perspective on protein complexes and also large numbers of interactions and increased statistical power, we need to consider alternative definitions of protein complexes to substantiate the above result. So, we next investigated experimentally derived protein complexes.
Paralogous subunits in protein complexes
We tested the corollary that there is an over-representation of interactions between paralogous proteins within protein complexes. We considered two distinct types of protein complex data. The first is composed of three independent data sets of protein complexes in S. cerevisiae (Table 1) and is discussed in this section; the second is composed of protein complexes of known three-dimensional structure, and will be considered in the next section.
Thus, analysis of the three sets of S. cerevisiae protein complex datasets supports the corollary that interacting paralogues are over-represented amongst protein complexes.
Paralogous subunits in protein complexes of known 3D structure
Next we concentrated on the set of protein complexes with known three- dimensional structure (Table 1) to further test the corollary that there is an over-representation of interfaces between paralogues within each protein complex. This dataset, obtained from the PQS database, is an automatically generated subset of the PDB containing solely oligomers . In PQS, the proportion of complexes with paralogues is comparable to the S. cerevisiae complex datasets, at 30% (Figure 4b). The advantage of studying this dataset is that it can provide stoichiometry and interaction maps for complexes, that is, we can test directly whether paralogues interact.
To further investigate this, we repeated the experiment shown in Figure 5a, but considering only subunits that can establish homo-interactions as well as interactions between paralogues. This is equivalent to determining what choice is made in a situation such as that represented in Figure 5b. We found that given a choice, in almost all cases a preference for interactions between paralogues will be made, as shown in Figure 5c. The reason for this is likely to be that this type of geometrical arrangement of proteins within complexes requires the smallest number of different interfaces to be formed, and so is the most parsimonious evolutionary scenario. In the F1 sub-complex, the three α and three β subunits alternate within the hexameric ring , so that only two different interfaces are formed (α:β and β:α; Figure 5b, left).
Evolutionary cores of protein complexes and asymmetry
Our hypothesis is that many protein complexes start with homomeric interactions that duplicate and diversify, and serve as a seed for the coalescence of further subunits. The photosystem I shown in Figure 1 illustrates this concept. In Heliobacteria, the complex contains a homodimer at its core (PshA2), whereas the eukaryotic complex contains a dimer of paralogues (PsaA:PsaB). These two paralogous polypeptide chains are each decorated by different peripheral subunits, suggesting that in this class of photosystem (Type-I RC), the core was established prior to the accretion of further subunits [21, 22]. Another example is RNA polymerase II, which contains at its core a large dimer of homologous subunits, and is believed to have evolved from an ancestral generic nucleic acid binding homodimer [31, 32].
To investigate whether this is a frequent mechanism of evolution of complexes, we tested the fifth corollary and asked whether homomeric interactions and interactions between homologous proteins precede interactions between unrelated proteins in evolution. Then we tested whether paralogues within complexes of known three-dimensional structure have asymmetric interactions.
Conservation of yeast protein interactions
To test whether paralogous proteins break the symmetry of a complex and allow accretion of different types of subunits, we considered the protein complexes of known three-dimensional structure again. We compared the set of complexes that contain paralogues to the complexes that contain homomeric interactions and no paralogues. As shown in Figure 5d, we found that 32% of paralogues have asymmetrical interactions, while only 4% of the homomers do, a significant difference (p < 0.001). Thus, the hypothesis that duplication of homomers results in new asymmetrical complexes is supported by the data. This may represent part of the selective advantage for conservation of such duplications.
We present here a genome-wide, cross-species analysis of the origins and evolution of protein complexes. At the beginning, we hypothesized that duplication of self-interacting proteins (homomers) is an evolutionary path leading to the establishment and evolution of many complexes. To substantiate this hypothesis, we tested five corollaries that arise from such an evolutionary scenario.
The first corollary is that duplication of genes coding for homodimers is frequently accompanied by conservation of protein interactions. Conservation of protein interactions after gene duplication has been shown to be frequent [9, 19]. We show here that between 4% and 13% of interactions in PINs are between paralogous proteins.
Next we tested the association between clustering of the network and interactions between paralogous proteins. Clusters in protein interaction networks frequently represent protein complexes. We have shown that removal of interactions between paralogues causes a small but highly significant decrease in the global clustering level of the network. This is consistent with our theoretical modeling results.
We then observed that about 30% of protein complexes from proteomics experiments contain duplicated subunits. In protein complexes of known three-dimensional structure, a similar proportion of complexes have duplicated subunits, and more importantly, there is preferential binding of paralogous subunits. This supports the corollary that interactions between paralogues are frequent in complexes.
We observed that proteins involved in homomeric interactions and interactions between paralogues were more conserved than other proteins: more than half of yeast proteins had orthologues in all eukaryotes and either archaea or bacteria, whereas more than half of the other yeast proteins had orthologues only in fungi and animals. Homomeric interactions and those between paralogous proteins were also three to seven times more likely to be conserved, when compared to other interactions. Thus, this supports the corollary that homomers and oligomers of paralogues represent the first steps in the evolution of new protein complexes, with other subunits added later.
Finally, we showed that amongst three-dimensional structures of complexes, 32% of dimers of paralogues establish asymmetric interactions with other proteins whereas only 3% of homodimers show such asymmetry, further substantiating that the duplication of homomeric interactions helps to create asymmetry in protein interactions, and allows the coalescence of other subunits in the complex.
Altogether, our data suggest an evolutionary route to the formation and specialization of many extant protein complexes. On this route, homomers and oligomers of paralogous subunits represent an ancestral core around which further subunits can coalesce in evolution. Sequence divergence of the paralogous subunits creates the asymmetry that permits the accretion and diversification of interactions. In addition, divergence of paralogues may be involved in functional specialization of complexes. The biases inherent in each data type make it difficult to determine the exact fraction of protein complexes that evolved via the proposed route. A higher bound is about one-third, estimated by the fraction of proteomics complexes that display duplicated subunits. A lower bound is less than one-tenth, estimated by the fraction of dimers of paralogues in one of the yeast two-hybrid data sets (Table 1).
Another issue that at this stage is difficult to ascertain is the nature of the complexes that emerged by the proposed route. If we assume that both the proteomics data and the crystallographic data represent an enrichment for stable protein complexes, then our proposed evolutionary route appears to be more prevalent in stable complexes. In fact, most examples discussed in the text are stable complexes. They also appear to be complexes that were established very early in evolution, which is illustrated by the ages of the proteins that establish homomeric interactions and interactions between duplicates.
We have shown previously that duplication of protein interactions and of entire protein complexes is accompanied by specialization of function . Inspection of the effects of duplication of homo-interactions suggests a similar outcome. In other words, the main function is established when the homomer is first formed, and then duplications will serve to specialize these functions. For example, in Figure 3a the transition from homodimer to dimers of paralogous proteins of the helix-turn-helix transcription factors results in specialization of the function of the complex, that is, distinct but overlapping specificities in DNA binding [34, 35]. Other examples of functional specialization are in the ATP synthase and proteosome families, as discussed in Additional data file 1.
Our investigations of protein interactions and protein complexes, as well as theoretical modeling, reveal that many protein complexes evolved by the initial establishment of self-interactions followed by duplication of these self-interacting proteins. Our study provides the first insight into the evolution of functional modularity in protein-protein interaction networks, and the origins of a large class of protein complexes.
Materials and methods
Datasets of protein interactions and protein complexes
Binary physical protein-protein interactions for S. cerevisiae [36, 37], Drosophila melanogaster (high confidence interactions)  and Caenorhabditis elegans. , as well as protein complex datasets for S. cerevisiae [36, 40, 41] and complexes of known three-dimensional structure used in this study  are summarized in Table 1.
A non-redundant set of protein complexes of known structure, based on the PQS database as of June 2005, was prepared by considering complexes as graphs where nodes are the protein subunits (labeled by the domain architecture and chain identity) and edges are a contact between these subunits: two complexes were considered identical when they had the same subunits (same domain architectures, that is, identical or homolgous chains) and the same contact topology between subunits. Details of this procedure can be found in .
Detection of gene duplication and contacts between chains
We used domain architecture as defined in the Superfamily database [43, 44] to identify paralogous proteins in PINs, that is, those proteins resulting from duplication of the corresponding genes. The SUPERFAMILY database provides protein domain assignments, at the SCOP 'superfamily' level , for the predicted protein sequences in completed genomes. Domain assignments were generated using a curated set of profile hidden Markov models. In this work, two proteins are considered paralogous if they display the same amino- to carboxy-terminal domain architecture, ignoring gaps and tandem domain repetitions as described in . Domain assignments were based on Superfamily release 1.63 .
In the analysis of protein complexes from PQS we considered two chains to be identical when strict sequence identity was found, and accepted gaps at the amino and carboxyl termini of the sequences. Two chains were considered homologous when they displayed the same amino- to carboxy-terminal SCOP superfamily domain architecture, and to be different when they did not satisfy any of the above criteria. We used a cut-off of five amino acids with atoms within their van der Waal's radii plus 0.5 Å for two chains to be considered in contact. The expected frequency for a given chain to form a homo- or a paralogous contact (Ph and Pp, respectively) within a complex was calculated by counting the number of times the given chain made one or more homo- or paralogous contacts (Nh and Np, respectively) in a set resulting from 500 randomizations of that protein complex. Randomizations consisted of considering the topology of each complex fixed, and shuffling the position of each chain within the complex. The expected frequencies were estimated by Ph = Nh/500 and Pp = Np/500.
To investigate the effect of correlations in the network in terms of evolutionary relationships or topological organization, the following randomization schemes were applied.
Randomization by domain architecture shuffling
To test for statistical significance of the measured parameters, we performed 10,000 network randomizations, in which the topology of the network was kept constant, and the evolutionary relationships between proteins, that is, their Superfamily domain assignments, were shuffled.
Randomization by link shuffling
To measure the influence of local organization of network structure, link shuffling was used . Repeated swapping of interaction partners among pairs of interacting proteins preserves the degree of each individual node in the network but destroys higher order topological correlations and structures such as clustering.
Modeling of the growth of the network by gene duplication
We implemented a theoretical model of network evolution based on the concepts proposed in [11, 25, 26]. In this model we started with x = 340 proteins, representing the total number of 241 protein families and 29% of unassigned proteins in the Yeast dataset. We randomly introduced an interaction between any pair of proteins with a probability 0.0059 = 2/339, leading to a classic random graph with a Poissonian degree distribution and an average degree of two. The network is then allowed to grow until it reaches the same size as the Yeast network (neglecting isolated nodes generated during the simulation). The parameter δ for the probability to delete a link under duplication and α for random re-linking of a new node to older nodes in the network was chosen with the aim of obtaining realistic network features (that is, degree distribution) in the final network, that is δ = 0.9 and α = 0 or α = 0.1. For more details, see Supplementary information S2 in Additional data file 1.
We used Smith-Waterman alignments to identify orthologs of yeast genes in the genomes of 40 organisms, representing the three branches of the tree of life, and the major taxonomical groups within each of the branches. We used the Smith-Waterman implementation of the TimeLogic's DeCypher® accelerated hardware. The significance of each hit is based on a PSCORE statistic where the p value is a real number between 0 and 1 describing the probability of a hit being random. The significance is based on the histogram fitting method and we used a cutoff of p < 0.01. A complete list of the organisms studied is shown in Additional data file 1 (Supplementary material S5). We considered two proteins to be orthologous if they were bidirectional best hits. The 'age' groups we can define based on available genomes are, starting from the most recent, 'S. cerevisiae specific'; 'Saccharomyceta'; 'Fungi'; 'Fungi/Metazoa'; 'Fungi/Metazoa/Amoebozoa'; 'Eukaryota'; 'Eukaryota+Archaea' or 'Eukaryota+Bacteria'; 'universal'. The eukaryotic tree used as reference is that in .
Additional data files
We are grateful for the hospitality and scientific discussions on networks that CK experienced with the members of the physics department at Imperial College, London, and the University of Oslo. We wish to thank Joel Janin, Daniela Stock, Kiyoshi Nagai, Tony Crowther, Cyrus Chothia, Benjamin Audit and the members of the Theoretical and Computational Biology group at the MRC-LMB for useful discussions. We are grateful to Nick Luscombe, Madan Babu, Christine Vogel, Valerie Hindie, Siarhei Maslau and Patrick Aloy for critical reading of the manuscript. We thank the MRC, EMBO, and the postdoctoral program of the German Academic Exchange Service (DAAD) for funding.
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