The 3D-partner is a web tool to predict interacting partners and binding models of a query protein sequence through structure complexes and a new scoring function. 3D-partner first utilizes IMPALA to identify homologous structures (templates) of a query from a heterodimer profile library. The interacting-partner sequence profiles of these templates are then used to search interacting candidates of the query from protein sequence databases (e.g. SwissProt) by PSI-BLAST. We developed a new scoring function, which includes the contact-residue interacting score (e.g. the steric, hydrogen bonds, and electrostatic interactions) and the template consensus score (e.g. couple-conserved residue and the template similarity scores), to evaluate how well the interfaces between the query and interacting candidates. Based on this scoring function, 3D-partner provides the statistic significance, the binding models (e.g. hydrogen bonds and conserved amino acids) and functional annotations of interacting partners. The correlation between experimental energies and predicted binding affinities of our scoring function is 0.91 on 275 mutated residues from the ASEdb. The average precision of the server is 0.72 on 563 queries and the execution time of this server for a query is ∼15 s on average. These results suggest that the 3D-partner server can be useful in protein-protein interaction predictions and binding model visualizations. The server is available online at: http://3D-partner.life.nctu.edu.tw.
As an increasing number of reliable protein–protein interactions (PPIs) become available and high-throughput experimental methods provide systematic identification of PPIs, there is a growing need for fast and accurate methods for discovering homologous PPIs of a newly determined PPI. PPISearch is a web server that rapidly identifies homologous PPIs (called PPI family) and infers transferability of interacting domains and functions of a query protein pair. This server first identifies two homologous families of the query, respectively, by using BLASTP to scan an annotated PPIs database (290 137 PPIs in 576 species), which is a collection of five public databases. We determined homologous PPIs from protein pairs of homologous families when these protein pairs were in the annotated database and have significant joint sequence similarity (E ≤ 10−40) with the query. Using these homologous PPIs across multiple species, this sever infers the conserved domain–domain pairs (Pfam and InterPro domains) and function pairs (Gene Ontology annotations). Our results demonstrate that the transferability of conserved domain-domain pairs between homologous PPIs and query pairs is 88% using 103 762 PPI queries, and the transferability of conserved function pairs is 69% based on 106 997 PPI queries. The PPISearch server should be useful for searching homologous PPIs and PPI families across multiple species. The PPISearch server is available through the website at http://gemdock.life.nctu.edu.tw/ppisearch/.
BackgroundComprehensive exploration of protein-protein interactions is a challenging route to understand biological processes. For efficiently enlarging protein interactions annotated with residue-based binding models, we proposed a new concept "3D-domain interolog mapping" with a scoring system to explore all possible protein pairs between the two homolog families, derived from a known 3D-structure dimmer (template), across multiple species. Each family consists of homologous proteins which have interacting domains of the template for studying domain interface evolution of two interacting homolog families.ResultsThe 3D-interologs database records the evolution of protein-protein interactions database across multiple species. Based on "3D-domain interolog mapping" and a new scoring function, we infer 173,294 protein-protein interactions by using 1,895 three-dimensional (3D) structure heterodimers to search the UniProt database (4,826,134 protein sequences). The 3D- interologs database comprises 15,124 species and 283,980 protein-protein interactions, including 173,294 interactions (61%) and 110,686 interactions (39%) summarized from the IntAct database. For a protein-protein interaction, the 3D-interologs database shows functional annotations (e.g. Gene Ontology), interacting domains and binding models (e.g. hydrogen-bond interactions and conserved residues). Additionally, this database provides couple-conserved residues and the interacting evolution by exploring the interologs across multiple species. Experimental results reveal that the proposed scoring function obtains good agreement for the binding affinity of 275 mutated residues from the ASEdb. The precision and recall of our method are 0.52 and 0.34, respectively, by using 563 non-redundant heterodimers to search on the Integr8 database (549 complete genomes).ConclusionsExperimental results demonstrate that the proposed method can infer reliable physical protein-protein interactions and be useful for studying the protein-protein interaction evolution across multiple species. In addition, the top-ranked strategy and template interface score are able to significantly improve the accuracies of identifying protein-protein interactions in a complete genome. The 3D-interologs database is available at http://3D- interologs.life.nctu.edu.tw.
A module is a group of closely related proteins that act in concert to perform specific biological functions through protein–protein interactions (PPIs) that occur in time and space. However, the underlying module organization and variance remain unclear. In this study, we collected module templates to infer respective module families, including 58,041 homologous modules in 1,678 species, and PPI families using searches of complete genomic database. We then derived PPI evolution scores and interface evolution scores to describe the module elements, including core and ring components. Functions of core components were highly correlated with those of essential genes. In comparison with ring components, core proteins/PPIs were conserved across multiple species. Subsequently, protein/module variance of PPI networks confirmed that core components form dynamic network hubs and play key roles in various biological functions. Based on the analyses of gene essentiality, module variance, and gene co-expression, we summarize the observations of module organization and variance as follows: 1) a module consists of core and ring components; 2) core components perform major biological functions and collaborate with ring components to execute certain functions in some cases; 3) core components are more conserved and essential during organizational changes in different biological states or conditions.
A module is a fundamental unit forming with highly connected proteins and performs a certain kind of biological functions. Modules and module–module interaction (MMI) network are essential for understanding cellular processes and functions. The MoNetFamily web server can identify the modules, homologous modules (called module family) and MMI networks across multiple species for the query protein(s). This server first finds module candidates of the query by using BLASTP to search the module template database (1785 experimental and 1252 structural templates). MoNetFamily then infers the homologous modules of the selected module candidate using protein–protein interaction (PPI) families. According to homologous modules and PPIs, we statistically calculated MMIs and MMI networks across multiple species. For each module candidate, MoNetFamily identifies its neighboring modules and their MMIs in module networks of Homo sapiens, Mus musculus and Danio rerio. Finally, MoNetFamily shows the conserved proteins, PPI profiles and functional annotations of the module family. Our results indicate that the server can be useful for MMI network (e.g. 1818 modules and 9678 MMIs in H. sapiens) visualizations and query annotations using module families and neighboring modules. We believe that the server is able to provide valuable insights to determine homologous modules and MMI networks across multiple species for studying module evolution and cellular processes. The MoNetFamily sever is available at http://monetfamily.life.nctu.edu.tw.
The proteins in a cell often assemble into complexes to carry out their functions and play an essential role of biological processes. The PCFamily server identifies template-based homologous protein complexes [called protein complex family (PCF)] and infers functional modules of the query proteins. This server first finds homologous structure complexes of the query using BLASTP to search the structural template database (11 263 complexes). PCFamily then searches the homologous complexes of the templates (query) from a complete genomic database (Integr8 with 6 352 363 protein sequences in 2274 species). According to these homologous complexes across multiple species, this sever infers binding models (e.g. hydrogen-bonds and conserved amino acids in the interfaces), functional modules, and the conserved interacting domains and Gene Ontology annotations of the PCF. Experimental results demonstrate that the PCFamily server can be useful for binding model visualizations and annotating the query proteins. We believe that the server is able to provide valuable insights for determining functional modules of biological networks across multiple species. The PCFamily sever is available at http://pcfamily.life.nctu.edu.tw.
Objective Mesenchymal stem cells (MSCs) hold great therapeutic potential in morbidities associated with preterm birth. However, the molecular expressions of MSCs in preterm birth infants are not systematically evaluated. In this study, the dual‐omics analyses of umbilical‐cord (UC)‐derived MSCs to identify the dysregulated cellular functions are presented. Materials and methods The UC‐MSCs are collected from ten full‐term and eight preterm birth infants for microarray and iTRAQ‐based proteome profiling. Results The integrative analysis of dual‐omics data discovered 5615 commonly identified genes/proteins of which 29 genes/proteins show consistent up‐ or downregulation in preterm birth. The Gene Ontology analysis reveals that dysregulation of mitochondrial translation and cellular response to oxidative stress are mainly enriched in 290 differential expression proteins (DEPs) while the 412 differential expression genes (DEGs) are majorly involved in single‐organism biosynthetic process, cellular response to stress, and mitotic cell cycle in preterm birth. Besides, a 13‐protein module involving CUL2 and CUL3 is identified, which plays an important role in cullin‐RING‐based ubiquitin ligase complex, as potential mechanism for preterm birth. Conclusion The dual‐omics data not only provide new insights to the molecular mechanism but also identify panel of candidate markers associated with preterm birth.
BackgroundOne of the crucial steps toward understanding the associations among molecular interactions, pathways, and diseases in a cell is to investigate detailed atomic protein-protein interactions (PPIs) in the structural interactome. Despite the availability of large-scale methods for analyzing PPI networks, these methods often focused on PPI networks using genome-scale data and/or known experimental PPIs. However, these methods are unable to provide structurally resolved interaction residues and their conservations in PPI networks.ResultsHere, we reconstructed a human three-dimensional (3D) structural PPI network (hDiSNet) with the detailed atomic binding models and disease-associated mutations by enhancing our PPI families and 3D–domain interologs from 60,618 structural complexes and complete genome database with 6,352,363 protein sequences across 2274 species. hDiSNet is a scale-free network (γ = 2.05), which consists of 5177 proteins and 19,239 PPIs with 5843 mutations. These 19,239 structurally resolved PPIs not only expanded the number of PPIs compared to present structural PPI network, but also achieved higher agreement with gene ontology similarities and higher co-expression correlation than the ones of 181,868 experimental PPIs recorded in public databases. Among 5843 mutations, 1653 and 790 mutations involved in interacting domains and contacting residues, respectively, are highly related to diseases. Our hDiSNet can provide detailed atomic interactions of human disease and their associated proteins with mutations. Our results show that the disease-related mutations are often located at the contacting residues forming the hydrogen bonds or conserved in the PPI family. In addition, hDiSNet provides the insights of the FGFR (EGFR)-MAPK pathway for interpreting the mechanisms of breast cancer and ErbB signaling pathway in brain cancer.ConclusionsOur results demonstrate that hDiSNet can explore structural-based interactions insights for understanding the mechanisms of disease-associated proteins and their mutations. We believe that our method is useful to reconstruct structurally resolved PPI networks for interpreting structural genomics and disease associations.Electronic supplementary materialThe online version of this article (10.1186/s12918-018-0537-2) contains supplementary material, which is available to authorized users.
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