Structural Perspectives on the Evolutionary Expansion of Unique Protein-Protein Binding Sites

Abstract

Structures of protein complexes provide atomistic insights into protein interactions. Human proteins represent a quarter of all structures in the Protein Data Bank; however, available protein complexes cover less than 10% of the human proteome. Although it is theoretically possible to infer interactions in human proteins based on structures of homologous protein complexes, it is still unclear to what extent protein interactions and binding sites are conserved, and whether protein complexes from remotely related species can be used to infer interactions and binding sites. We considered biological units of protein complexes and clustered protein-protein binding sites into similarity groups based on their structure and sequence, which allowed us to identify unique binding sites. We showed that the growth rate of the number of unique binding sites in the Protein Data Bank was much slower than the growth rate of the number of structural complexes. Next, we investigated the evolutionary roots of unique binding sites and identified the major phyletic branches with the largest expansion in the number of novel binding sites. We found that many binding sites could be traced to the universal common ancestor of all cellular organisms, whereas relatively few binding sites emerged at the major evolutionary branching points. We analyzed the physicochemical properties of unique binding sites and found that the most ancient sites were the largest in size, involved many salt bridges, and were the most compact and least planar. In contrast, binding sites that appeared more recently in the evolution of eukaryotes were characterized by a larger fraction of polar and aromatic residues, and were less compact and more planar, possibly due to their more transient nature and roles in signaling processes.

CoRNeA: A pipeline to decrypt the inter protein interfaces from amino acid sequence information

“…Since the eukaryotic proteins are not exclusive to only one set of function, it has been perceived that most of the eukaryotic protein interactions are transient, having smaller interaction hotspot zones and have more planar binding sites consisting of more polar and aromatic residues. These properties of the eukaryotic protein interactions make them essential part of cell signaling pathways (Goncearenco et al 2015).…”

Exploring Protein-Protein Interactions as Drug Targets for Anti-cancer Therapy with In Silico Workflows

“…Studies on PPI binding site properties go back several decades, and some of them reported an extensive similarity between protein interfaces even in the absence of sequence or structure similarity between proteins [12–15]. Since the current coverage of the human proteome with protein structural complexes remains limited, and the number of novel PPI binding sites in the PDB database grows slower than the number of protein complexes [16, 17], different computational methods have been proposed to close this gap. It has been shown that protein interactions and binding sites for human complexes can be predicted from homologous protein structural complexes of another species [18–20].…”

“…It has been shown that protein interactions and binding sites for human complexes can be predicted from homologous protein structural complexes of another species [18–20]. Such an inference approach may be supported by a recent work that examined the growth dynamics and evolutionary roots of PPI binding sites and found that a majority of binding sites could be traced back to the universal common ancestor of all cellular organisms [16]. …”

Comparative analyses of quaternary arrangements in homo-oligomeric proteins in superfamilies: Functional implications

“…Evolution and physicochemical properties of binding sites in biological units of homo-oligomers have been studied by clustering based on sequence and structure. 13 These structural and evolutionary studies have led to an interolog approach, wherein conserved structures of homologous pairs of interacting proteins across different organisms are exploited in the prediction of interface residues in homo-oligomeric proteins of unknown structure using their homologues of known structure. 14 The protein subunit interactions stabilises the interacting interfaces and prevents the formation of aberrant assemblies.…”

“…Oligomeric states, interface residues, and binding modes are known to be conserved in closely related homo‐oligomers. Evolution and physicochemical properties of binding sites in biological units of homo‐oligomers have been studied by clustering based on sequence and structure . These structural and evolutionary studies have led to an interolog approach, wherein conserved structures of homologous pairs of interacting proteins across different organisms are exploited in the prediction of interface residues in homo‐oligomeric proteins of unknown structure using their homologues of known structure .…”