SUMMARY: Proteins frequently function as parts of complexes, assemblages of multiple proteins and other biomolecules, yet network visualizations usually only show proteins as parts of binary interactions. ComplexViewer visualizes interactions with more than two participants and thereby avoids the need to first expand these into multiple binary interactions. Furthermore, if binding regions between molecules are known then these can be displayed in the context of the larger complex. AVAILABILITY AND IMPLEMENTATION: freely available under Apache version 2 license; EMBL-EBI Complex Portal: http://www.ebi.ac.uk/complexportal; Source code: https://github.com/MICommunity/ComplexViewer; Package: https://www.npmjs.com/package/complexviewer; http://biojs.io/d/complexviewer. Language: JavaScript; Web technology: Scalable Vector Graphics; Libraries: D3.js. CONTACT: colin.combe@ed.ac.uk or juri.rappsilber@ed.ac.uk

Combe, Colin W

Heimbach, Joshua

Hermjakob, Henning

Meldal, Birgit HM

Micklem, Gos

Orchard, Sandra

Rappsilber, Juri

Sivade, Marine Dumousseau

English

Apollo (Cambridge)

Systems biologyComplexViewer: visualization of curatedmacromolecular complexesColin W. Combe1,*, Marine (Dumousseau) Sivade2,Henning Hermjakob2, Joshua Heimbach3,4, Birgit H. M. Meldal2,Gos Micklem3,4, Sandra Orchard2 and Juri Rappsilber1,5,*1Wellcome Trust Centre for Cell Biology, School of Biological Sciences, University of Edinburgh, Edinburgh,EH9 3BF, UK, 2European Bioinformatics Institute (EMBL-EBI), European Molecular Biology Laboratory, WellcomeGenome Campus, CB10 1SD, Cambridge, UK, 3Cambridge Systems Biology Centre, University of Cambridge,Cambridge, CB2 1QR, UK, 4Department of Genetics, University of Cambridge, Cambridge, CB2 3EH, UK and 5Chairof Bioanalytics, Department of Bioanalytics, Institute of Biotechnology, Technische Universita¨t Berlin, Berlin,13355, Germany*To whom correspondence should be addressed.Associate Editor: Jonathan WrenReceived on June 2, 2017; revised on July 21, 2017; editorial decision on July 29, 2017; accepted on August 1, 2017AbstractSummary: Proteins frequently function as parts of complexes, assemblages of multiple proteinsand other biomolecules, yet network visualizations usually only show proteins as parts of binaryinteractions. ComplexViewer visualizes interactions with more than two participants and therebyavoids the need to first expand these into multiple binary interactions. Furthermore, if bindingregions between molecules are known then these can be displayed in the context of the largercomplex.Availability and implementation: freely available under Apache version 2 license; EMBL-EBI Complex Portal: http://www.ebi.ac.uk/complexportal; Source code: https://github.com/MICommunity/ComplexViewer; Package: https://www.npmjs.com/package/complexviewer; http://biojs.io/d/complexviewer. Language: JavaScript; Web technology: Scalable Vector Graphics;Libraries: D3.js.Contact: colin.combe@ed.ac.uk or juri.rappsilber@ed.ac.uk1 IntroductionA wide variety of experimental techniques are used to investigate themolecular interactions that drive and regulate cellular processes. Forexample, a gel filtration experiment identifies groups of associatedproteins—these are not necessarily binary interactions, and to ex-pand them into multiple binary interactions for the purpose of net-work visualization introduces false positives. ComplexVieweravoids the need for this expansion and provides a more biologicallyrealistic representation of the interaction.The IMEx Consortium (Orchard et al., 2012) is an internationalcollaboration designed to systematically capture published inter-action data in publicly available databases. The IMEx Consortiumuses the Proteomics Standards Initiative-Molecular Interaction(PSI-MI) data standards to enable the reuse and exchange of data(Hermjakob et al., 2004; Kerrien et al., 2007). These standardscapture a high level of detail to allow a dynamic view of the cellularenvironment, for example, recording n-ary not just binary inter-actions. However, no viewer exists which can support all the infor-mation curated into an IMEx record.The European Bioinformatics Institute (EMBL-EBI) has de-veloped the Complex Portal (http://www.ebi.ac.uk/complexportal),an encyclopaedia of manually curated macromolecular complexesthat captures the biologically functional units of proteins and otherparticipating molecules by amalgamating experimental informationand assorted background information (Meldal et al., 2015). TheComplex Portal data are stored in the IntAct database (KerrienVC The Author 2017. Published by Oxford University Press. 3673This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/), which permitsunrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited.Bioinformatics, 33(22), 2017, 3673–3675doi: 10.1093/bioinformatics/btx497Advance Access Publication Date: 3 August 2017Applications Noteet al., 2012; http://www.ebi.ac.uk/intact) and conform to PSI-MIstandards.The Complex Portal website requires a visualization that can ac-curately represent the following aspects of PSI-MI data: interactionswith more than two participants (n-ary interactions); sequence fea-tures relevant to the interaction, such as binding domains; a range ofbiomolecules as interactor types (proteins, small molecules, nucleicacids); discontinuous sequence features; and, stoichiometry informa-tion. ComplexViewer meets these needs and provides 2D diagramsof the topology of the rapidly increasing number of complexesdescribed by this resource.2 ImplementationPSI-MI data standards come in two distinct formats—XML basedand tab-delimited. The tab-delimited format is not a suitable basisfor the ComplexViewer because (i) it removes the information onhow specific binding regions interact, and (ii) cannot record inter-actions with more than two participants. The XML format fullycaptures the detail of n-ary interactions but is not designed for pars-ing within browsers. To provide this detail in a concise, easy-to-parse format we designed the JavaScript Object Notation formatMI-JSON. At the 2017 HUPO PSI, the Molecular Interaction work-group decided MI-JSON will be its recommended protocol for serv-ing interaction data to web pages and visualization tools. MI-JSONcan be generated from any PSI-MI compliant data source using theJava Molecular Interactions library (JAMI, https://github.com/MICommunity/psi-jami, manuscript in preparation).ComplexViewer is derived from xiNET (Combe et al., 2015),which already contained functionality for displaying pairs of linkedresidues but could not display binding regions nor support n-aryinteractions.3 Results and discussionComplexViewer can display macromolecular complexes of varyingsize while preserving their internal topology, binding features andstoichiometry. Figure 1 shows two examples from the EMBL-EBIComplex Portal.The Mitochondrial pyruvate dehydrogenase complex is one ofthe largest structures in the Complex Portal. Displaying its 136 indi-vidual protein molecules would overwhelm the view and thereforefor complexes in which any participant has a stoichiometry of morethan 30, the stoichiometry is collapsed and displayed in squarebrackets. This example also highlights the varying levels of informa-tion available for the internal topology, with detailed binding fea-tures available for LAT1 (odp2) and PDX1 (odpx). TheHaemoglobin HbA complex is much smaller which allowsComplexViewer to display it with its stoichiometry expanded and aclearly defined internal topology.In addition to the Complex Portal, ComplexViewer has beenincorporated into HumanMine (Smith et al., 2012; http://www.humanmine.org) and YeastMine (Balakrishnan et al., 2012; http://yeastmine.yeastgenome.org), which are data warehouses of modelorganism information, and also into the IntAct Editor (Orchardet al., 2014; https://github.com/EBI-Intact/intact-editor). The IntActEditor is a tool designed to assist with the curation process; provid-ing a more detailed visualization has enabled more accurate andcomplete curation.4 ConclusionComplexViewer is proving a useful tool for visualizing molecularinteraction data. We intend to extend its functionality to show thehierarchical nesting of complexes and the full range of PSI-MI datafor curated experimental evidence, such as is stored in IntAct(Kerrien et al., 2012). The main challenge in extending the applic-ability of ComplexViewer will be allowing the navigation of largernetworks, comprised of many such n-ary interactions. We thinkachieving this goal would be a beneficial step away from the n-aryto binary expansion procedures which, in essence, add false dataprior to visualization.FundingThis work was supported by the Wellcome Trust [103139 to J.R., 063412 toH.H., J.R.]; and the BBSRC [BB/L024179/1 to S.O., G.M. and H.H.].Wellcome Trust Centre for Cell Biology is supported by core funding fromthe Wellcome Trust [203149].Conflict of Interest: none declared.ReferencesBalakrishnan,R. et al. (2012) YeastMine—an integrated data warehouse forSaccharomyces cerevisiae data as a multipurpose tool-kit. Database(Oxford), 2012, bar062.Fig. 1. (i) EBI-9691559: Mitochondrial pyruvate dehydrogenase complex. Thecomplex (in blue) is a single n-ary interaction in which interactions betweencertain participants are known and some binding sites are known.Stoichiometry information is given in square brackets. (ii) EBI-9008420:Haemoglobin HbA complex. This complex is shown both with the stoichiom-etry information collapsed (left) and expanded (right)3674 C.W.Combe et al.Combe,C.W. et al. (2015) xiNET: cross-link network maps with residue reso-lution. Mol. Cell. Proteom., 14, 1137–1147.Hermjakob,H. et al. (2004) The HUPO PSI’s Molecular Interaction format—acommunity standard for the representation of protein interaction data. Nat.Biotechnol., 22, 177–183.Kerrien,S. et al. (2007) Broadening the horizon—level 2.5 of the HUPO-PSIformat for molecular interactions. BMC Biol., 5, 44.Kerrien,S. et al. (2012) The IntAct molecular interaction database in 2012.Nucleic Acids Res., 40, D841–D846.Meldal,B.H.M. et al. (2015) The complex portal—an encyclopaedia of macro-molecular complexes. Nucleic Acids Res., 43, D479–D484.Orchard,S. et al. (2012) Protein interaction data curation: the InternationalMolecular Exchange (IMEx) consortium. Nat. Methods, 9, 345–350.Orchard,S. et al. (2014) The MIntAct project—IntAct as a common curationplatform for 11 molecular interaction databases. Nucleic Acids Res., 42,D358–D363.Smith,R. et al. (2012) InterMine: a flexible data warehouse system for the inte-gration and analysis of heterogeneous biological data. Bioinformatics, 28,3163–3131.ComplexViewer 3675

ComplexViewer: visualization of curated macromolecular complexes.

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ComplexViewer: visualization of curated macromolecular complexes.

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