1. The Complex Portal: A ‘one-stop shop’ for protein complexes Birgit Meldal IntAct Curator bmeldal@ebi.ac.uk

2. Rational 1. Most protein-protein interaction (PPI) databases display PPIs as binary interactions - to allow user-friendly displays in web interfaces (tables) to allow building of protein networks but, this means loosing the information of the in vivo topology of multi-protein complexes 2. There was no central database that amalgamated information about protein complexes from their constituent parts to their molecular function and involvement in biological processes. Many databases included snippets of such information but were lacking cross-references or lost financial support to update the database Complex Portal @ Networks & Pathways Course, EBI, 9th June 2014

3. Objectives To design an Online Portal to search and visualise protein complexes Including cross-referencing to source databases and beyond Export to interested parties in a format of their choice Incorporate the data into network analysis tools Emphasis on major model organisms, chosen to span the taxonomic range – Homo sapiens, Mus musculus, Saccharomyces cerevisiae, Escherichia coli Caenorhabditis elegans, Drosophila melanogaster, Saccharomyces pombe, Arabidopsis thaliana All data held in IntAct DB but separated from experimental evidence Complex Portal @ Networks & Pathways Course, EBI, 9th June 2014

4. Definition of stable complexes A stable set (2 or more) of interacting protein molecules which can be co-purified and have been shown to exist as a functional unit in vivo. Non-protein molecules (e.g. small molecules, nucleic acids) may also be present in the complex. Complex Portal @ Networks & Pathways Course, EBI, 9th June 2014

5. What is not a stable complex? 1. Enzyme/substrate, receptor/ligand or similar transient interactions, Unless: one element is a complex in its own right and/or it is an obligate complex that requires substrate/ligand binding, e.g. PDGF receptors 2. Two proteins associated in a pulldown / coimmunoprecipitation with no functional link Complex Portal @ Networks & Pathways Course, EBI, 9th June 2014

6. Source Databases MatrixDB (Sylvie Richard-Blum, Univ. of Lyon) Mining UniProt – yeast (Bernd Roechert, SIB – manually) PDBe (EBI) ChEMBL (EBI) Reactome – human (EBI) Manual curation from IMEx DBs & the literature (Sandra & Birgit) User requests (prioritised!) Complex Portal @ Networks & Pathways Course, EBI, 9th June 2014

7. Data captured Participants proteins (UniProt) small molecules (ChEBI) nucleic acids (Ensembl, ChEBI, RNACentral?) Species (visible in search results) Stoichiometry – when known Topology (= binding sites) – when known Complex Portal @ Networks & Pathways Course, EBI, 9th June 2014

8. Data captured Complex-specific, free-text annotation fields: Function and context – UniProt-style (visible in search results) Assembly, e.g. homodimer, heterotetramer… Physical properties, e.g. MW, size, topology/assembly Ligands Disease Complex Portal @ Networks & Pathways Course, EBI, 9th June 2014

9. Data captured Complex names: Recommended name: most recognisable name from literature, use GO component if specific complex exists in GO (visible in search results) Systematic name: based on Reactome’s new CV names – ‘string of gene names with stoichiometry’ Synonyms: all other names the complex may be known as Complex Portal @ Networks & Pathways Course, EBI, 9th June 2014

10. Data captured Structured annotation using GO (BP, MF, CC) Cross references to experimental evidence: IMEx (+ non-IMEx IntAct & DIP), PDB, EMDB Cross references to related complex data: Reactome (human) ChEMBL Intenz (enzyme EC numbers) OMIM / EFO / Orphanet (disease) ECO (evidence code ontology) PubMed (for further information) Complex Portal @ Networks & Pathways Course, EBI, 9th June 2014

11. ECO – Evidence Code Ontology ECO:0000353: physical interaction evidence used in manual assertion, if : full experimental evidence for the complexes is present either in a PPI DB, PDB or EMDB ECO:0000266: sequence orthology evidence used in manual assertion, if: only limited experimental evidence exists for a complex in one species (e.g. mouse) but it is desirable to curate the complex which has been curated in another species (e.g. human) and orthologous gene products exist in the former species, e.g. PDGFs ECO:0000250: sequence similarity evidence used in manual assertion, if: only limited experimental evidence exists for one complex but full experimental evidence exists for a similar complex of the same species ECO:0000306: inference from background scientific knowledge used in manual assertion, if: no or only partial experimental evidence can be found but the complexes are generally assumed to exist, e.g. GABA receptors exist in ChEMBL Complex Portal @ Networks & Pathways Course, EBI, 9th June 2014

12. Future plans More content! Other groups already voiced interest in joining our curation effort. We welcome any volunteer contributions and can train you and set you up on the system. Expand search filters / add Advanced Search: Species GO terms ECO Complex Portal @ Networks & Pathways Course, EBI, 9th June 2014

13. Future plans Visualisation: Schematic views Crystal / EM structures (PDBe / EMDB) Integration of pathway view (Reactome) Drug targets (ChEMBL) Small molecule structures & Ontology (ChEBI) Enzyme reactions (Rhea) Gene expression data (Expression Atlas) Direct link to search for related complexes and interactions Complex Portal @ Networks & Pathways Course, EBI, 9th June 2014

14. Live demo! www.ebi.ac.uk/intact/complex Complex Portal @ Networks & Pathways Course, EBI, 9th June 2014

15. Direct Submissions and Contact Complex Portal @ Networks & Pathways Course, EBI, 9th June 2014

16. Acknowledgements Complex Portal @ Networks & Pathways Course, EBI, 9th June 2014 Henning Hermjakob Group leader Sandra Orchard Coordinator Pablo Porras Milan Birgit Meldal Margaret Duesbury Curation team Marine Dumousseau Developing team Oscar Forner- Martinez bmeldal@ebi.ac.uk

17. Acknowledgements Complex Portal @ Networks & Pathways Course, EBI, 9th June 2014 GO Jane Lomax Paola Roncaglia David Osumi-Sutherland Rebecca Foulger Rachel Huntley Heiko Dietze SIB Bernd Roechert MatrixDB Sylvie-Ricard-Blum Reactome Steve Jupe David Croft ChEMBL Anna Gaulton Yvonne Light PDBe Sameer Velankar Jose Dana

18. Thank you! ? Complex Portal @ Networks & Pathways Course, EBI, 9th June 2014