Do protein–protein interaction databases identify moonlighting proteins?

Abstract

One of the most striking results of the human (and mammalian) genomes is the low number of protein-coding genes. To-date, the main molecular mechanism to increase the number of different protein isoforms and functions is alternative splicing. However, a less-known way to increase the number of protein functions is the existence of multifunctional, multitask, or ''moonlighting'', proteins. By and large, moonlighting proteins are experimentally disclosed by serendipity. Proteomics is becoming one of the very active areas of biomedical research, which permits researchers to identify previously unseen connections among proteins and pathways. In principle, protein-protein interaction (PPI) databases should contain information on moonlighting proteins and could provide suggestions to further analysis in order to prove the multifunctionality. As far as we know, nobody has verified whether PPI databases actually disclose moonlighting proteins. In the present work we check whether well-established moonlighting proteins present in PPI databases connect with their known partners and, therefore, a careful inspection of these databases could help to suggest their different functions. The results of our research suggest that PPI databases could be a valuable tool to suggest multifunctionality.Moonlighting proteins alternative functions are mostly related to cellular localization, cell type, oligomeric state and the cellular concentration of ligands, substrates, cofactors and products. [1][2][3][4][5] In any case, moonlighting will complicate the analysis and interpretation of protein networks of interactions, functional genomics, metabolomics, knock-out and iRNA phenotypes, genetic analysis of diseases, drug-target identification, toxicology and so on. Although some findings suggest involvement of a protein in extra functions, i.e., finding them in different cellular locations; in amounts exceeding those required for its catalytic known function, usually moonlighting proteins are experimentally disclosed by serendipity; therefore any alternative method to identify these proteins would be very valuable. In a previous work, the possibility of identifying moonlighting proteins by bioinformatics was explored by our group. 6 In the present work, we check whether the analysis of protein interacting partners of well-established moonlighting proteins can be reliable enough to disclose multifunctionality. Fig. 1 Scheme of the method used in this work.

Genome-scale identification and characterization of moonlighting proteins

“…These two studies suggest that secondary functions may be found in distantly related sequences if not in close homologs; however, further investigation is needed because the studies are based on a limited dataset. Gomez et al have also analyzed protein-protein interactions (PPIs) of moonlighting proteins and showed that GO terms of secondary function are enriched in interacting proteins, although they concluded that predicting correct secondary function from a PPI network is not an easy task [33]. Computational works on moonlighting proteins were recently summarized in a review article [34].…”

Genome-scale prediction of moonlighting proteins using diverse protein association information

“…First, they rely heavily on the existence of functional annotation of a protein (Chapple et al, 2015;Pritykin et al, 2015), which is a major bottleneck of the problem. Second, all the existing methods address different aspects of MPs' functional diversity: sequence similarity (Gomez et al, 2003;Khan et al, 2012), motifs/ domains, structural disorder (Hern andez et al, 2011), or proteinprotein interaction (PPI) patterns combined with existing gene ontology (GO) annotations (Chapple et al, 2015;G omez et al, 2011;Pritykin et al, 2015). However, the diverse nature of MPs' functions, cellular locations, function switching mechanisms, and the organisms in which they are found gives compelling evidence that in order to understand and identify the overall functional aspects of these proteins, one should characterize these proteins in a wider functional/proteomic space.…”

A non-catalytic role for inositol 1,3,4,5,6-pentakisphosphate 2-kinase in the synthesis of ribosomal RNA

“…The association of scaffolds with binding partners can arise from some unique properties of structurally disordered regions of proteins. Such domains have the flexibility to alter conformation and secondarystructure so as to make specific protein/protein interactions (Gómez et al, 2011). We do not know if this is the case for hIP5K, as its structure is not known.…”

“…It is now appreciated that alternate gene splicing has evolved on a large scale to provide multiplicity of protein functions. But there is a more unusual and often unpredictable evolutionary pathway to gene multifunctionality: 'moonlighting' (Gómez et al, 2011). This is a phenomenon whereby one protein acquires two roles that are strikingly independent of each other.…”