Metazoans evolved by taking domains from soluble proteins to expand intercellular communication network

Abstract

A central question in animal evolution is how multicellular animals evolved from unicellular ancestors. We hypothesize that membrane proteins must be key players in the development of multicellularity because they are well positioned to form the cell-cell contacts and to provide the intercellular communication required for the creation of complex organisms. Here we find that a major mechanism for the necessary increase in membrane protein complexity in the transition from non-metazoan to metazoan life was the new incorporation of domains from soluble proteins. The membrane proteins that have incorporated soluble domains in metazoans are enriched in many of the functions unique to multicellular organisms such as cell-cell adhesion, signaling, immune defense and developmental processes. They also show enhanced protein-protein interaction (PPI) network complexity and centrality, suggesting an important role in the cellular diversification found in complex organisms. Our results expose an evolutionary mechanism that contributed to the development of higher life forms.

Figure 1. Shared domains of membrane and soluble proteins in non-metazoan and metazoan genomes.

(a) Overlap analysis of membrane and soluble protein domains in yeast and human genomes. (b) The number (black bars) and fraction (white bars) of shared domains of membrane and soluble proteins in 5 non-metazoan and 5 metazoan genomes.

Figure 2. Examples of membrane proteins with shared domains that connect intercellular networks.

(a) LRR domains of leucine-rich repeat-containing proteins (NGL-2) interact with Laminet-2, DLG4 and NMDA receptors. (b) Phylogenetic profiles of LRR domains and their interaction partners in non-metazoan and metazoan species. A black dot indicates the presence of shared domains. A hollow dot indicates the absence of shared domains. (c) VWA domains of integrin alpha-L proteins (ITGAL) interact with ICAM1, ICAM2, ICAM3 and ICAM4. (d) Phylogenetic profiles of VWA domains and their interaction partners.

Figure 3. Network properties of membrane proteins with shared domains.

(a) The number of network connections (degree) of membrane proteins with and without shared domains were compared in the human PPI network. (b) Comparison of betweenness centrality of membrane proteins with and without shared domains. Error bars represent the standard error. (c) Comparison of the localization enrichment of the interaction partners of membrane proteins with and without shared domains. EXT indicates extracellular interaction partners and CYT indicates cytosolic interaction partners. (d) Topological orientation of shared domains in membrane proteins. ‘Out’ indicates the extracellular side and ‘in’ indicates the cytosolic side. The topology of shared domains was determined by combining the prediction results of TMHMM and location information of Pfam domains.

Figure 4. Functional enrichment of membrane proteins with and without shared domains.

The fraction of membrane proteins with and without shared domains was compared in functional categories using Gene Ontology (GO). Significantly enriched functional categories at GO level 2 and level 3 are shown (p-value < 1.0 × 10⁻⁴, hypergeometric test).