Roberto Mosca

Research interests

My research is focused on the analysis of protein-protein interaction networks using structural data in order to unveil the molecular details underlying cellular processes and help understand the mechanisms that govern complex biological systems in normal and anomalous states, like disease states.

Previous working experience

I have started developing my research in the structural bioinformatics field by analyzing and comparing ensembles of conformations of similar proteins. The work I did at the FIRC Institute of Molecular Oncology (IFOM), in Milan, and later at the European Molecular Biology Laboratory (EMBL), in Hamburg, has given me a deep understanding of the structural space of proteins and macromolecular complexes as well as the experimental techniques used to obtain such structural data (particularly X-ray crystallography). This first experience has culminated in the realization of a tool for the structural alignment and comparison of proteins in the presence of domain motions (RAPIDO, http://webapps.embl-hamburg.de/rapido/, Mosca et al 2008 BMC Bionformatics, Mosca et al 2008 Nucleic Acids Res).

With the move to the Institute of Research in Biomedicine (IRB), in Barcelona, I started applying my previous expertise to the field of Network Biology by combining structural data to protein-protein interaction networks. In this field I am actively pursuing two main objectives: creating tools for the structural annotation of interactomes and using the data they produce to help understand the molecular mechanisms of the underlying biological processes.

As for the first objective, I have explored all possible techniques for the structural modeling of protein-protein interactions and macromolecular complexes. My main contribution to this area has been the generation of a resource, called Interactome3D (Mosca et al 2013 Nat Methods, featured in the News and Views of the same issue, http://interactome3d.irbbarcelona.org), for the automatic structural annotation of protein-protein interaction datasets, which has grown into a reference resource in the field. This line of research has also led to the first high-throughput docking experiment on the yeast interactome (Mosca et al 2009 PLoS Comput Biol) and, more recently, to the investigation of the limits reachable by state-of-the-art techniques in enlarging the structural coverage of interactomes, focusing particularly on template based docking (Negroni, Mosca and Aloy 2014 Structure). Another important application of Interactome3D has been the analysis of the reliability of Y2H methods in a large-scale human interactome (Rolland, …, Mosca et al 2014 Cell).

As for the second objective, I have used structurally annotated networks for different types of analysis. For example, I analyzed the role of disorder in the evolution of protein-protein interaction networks (Mosca et al, Mol Cell Prot 2012), and studied the impact of cancer related mutations in BRCA1 (Quiles, …, Mosca et al 2013 PLoS ONE) and its interactions. Furthermore, I used structural interactomes to help mapping the internal topology of macromolecular complexes in Escherichia Coli (Rajagopala, …, Mosca et al 2014 Nat biotechnol) and build models of mitochondrial complexes in Yeast (Jin, …, Mosca et al 2014 J Proteome Res). Finally, my most important contribution to this area has been the creation of a resource for the mapping of mutations at the systemic level on the human structural interactome (dSysMap, http://dsysmap.irbbarcelona.org, Mosca et al 2015 Nat Methods).

Software tools

• dSysMap

  dSysMap is a resource for the systematic mapping of disease-related missense mutations on the human structural interactome. It summarizes mutational data in a systemic context, and provides a unique tool to the biologist to easily grab the molecular relationships between diseases and formulate hypotheses about their mechanism of action. In addition to the precompiled data for thousands of diseases in OMIM, dSysMap allows to upload newly discovered mutations so that disease context can be readily incorporated into primary sequencing studies. You can access the server at http://dsysmap.irbbarcelona.org.

• Interactome3D

  Interactome3D is a web service for the structural annotation of protein-protein interaction networks. You can submit your interactions and the server will find all the available structural data for both the single interactors and the interactions themselves. Additionally you can also visualize and download structural information for interactions involving a set of proteins or interactomes for nine model organisms. You can access the server at http://interactome3d.irbbarcelona.org.

• 3did

  The database of three-dimensional interacting domains (3did) is a collection of protein interactions for which high-resolution three-dimensional structures are known. 3did exploits the a availability of structural data to provide molecular details on interactions between two globular domains as well as novel domain–peptide interactions, derived using a recently published method from our lab. The interface residues are presented for each interaction type individually, plus global domain interfaces at which one or more partners (domains or peptides) bind. The 3did web server at http://3did.irbbarcelona.org visualizes these interfaces along with atomic details of individual interactions using Jmol.

• RAPIDO: Alignment of Protein Structures in the presence of Domain Movements

  RAPIDO stands for Rapid Alignment of Protein structures In the presence of Domain mOtions and is a tool for flexible structural alignment of protein structures. Flexible means that RAPIDO is able to align protein structures in the presence of conformational changes like rigid body movement between two or more domains or subdomains. It is also able to identify conformationally invariant parts between the two structures and to superimpose them on the basis of every identified rigid body.

Publications

Mateo L, Guitart-Pla O, Pons C, Duran-Frigola M, Mosca R, Aloy P. A PanorOmic view of personal cancer genomes, Nucleic Acids Res 2017, 45(April):195–200, doi:10.1093/nar/gkx311 [link]

Zhong Q, Pevzner SJ, Hao T, Wang Y, Mosca R, Menche J, et al. An inter-species protein-protein interaction network across vast evolutionary distance, Mol Syst Biol 2016, Apr 22;12(4):865–865, doi:10.15252/msb.20156484 [link]

Sfriso P, Duran-Frigola M, Mosca R, Emperador A, Aloy P, Orozco M. Residues Coevolution Guides the Systematic Identification of Alternative Functional Conformations in Proteins, Structure 2016, 24(1):116–26, doi:10.1016/j.str.2015.10.025 [link]

Kumar A, Beloglazova N, Bundalovic-Torma C, Phanse S, Deineko V, Gagarinova A, ..., Mosca R et al. Conditional Epistatic Interaction Maps Reveal Global Functional Rewiring of Genome Integrity Pathways in Escherichia coli, Cell Rep 2016, 14(3):648–61, doi:10.1016/j.celrep.2015.12.060 [link]

Yachie N, Petsalaki E, Mellor JC, Weile J, Jacob Y, Verby M, ..., Mosca R et al. Pooled-matrix protein interaction screens using Barcode Fusion Genetics, Mol Syst Biol 2016,12(4):863, doi:10.15252/msb.20156660 [link]

Mosca R, Tenorio-Laranga J, Olivella R, Alcalde V, Céol A, Soler-López M and Aloy P, dSysMap: exploring the edgetic role of disease mutations, 2015, Nature Methods, 12:167-168, doi:10.1038/nmeth.328 [link]

Jin K, Musso G, Vlasblom J, Jessulat M, Deineko V, Negroni J, Mosca R ... Aloy P, Zhang Z, Babu M, Yeast Mitochondrial Protein-Protein Interactions Reveal Diverse Complexes and Disease-Relevant Functional Relationships, Journal of Proteome Research, 2015, 14(2):1220-37, doi: 10.1021/pr501148q [link]

Rolland T, Taşan M, Charloteaux B, Pevzner SJ, Zhong Q, Sahni N, … Mosca R ... Aloy P ... Roth FP, Vidal M, A Proteome-Scale Map of the Human Interactome Network, Cell 2014, 159(5), 1212–1226, doi:10.1016/j.cell.2014.10.050 [link]

Negroni J, Mosca R and Aloy P, Assessing the Applicability of Template-Based Protein Docking in the Twilight Zone, Structure, 2014, Advanced Online Publication, doi:10.1016/j.str.2014.07.009 [link]

Häuser R, Ceol A, Rajagopala S, Mosca R, Siszler G, Wermke N, Sikorski P, Schwarz F, Schick M, Wuchty S, Aloy P and Uetz P, An Second-generation Protein-Protein Interaction Network of Helicobacter pylori, Mol Cell Proteomics 2014, 13(5):1318-29, doi:10.1074/mcp.O113.033571 [link]

Rajagopala S, Sikorski P, Kumar A, Mosca R, Vlasblom J, Arnold R, Franca-Koh J, Pakala S, Phanse S, Ceol A, Hauser R, Siszler G, Wuchty S, Emili A, Babu M, Aloy P, Pieper R, Uetz P, The binary protein-protein interaction landscape of Escherichia coli, Nature Biotechnology 2014, 32(3):285–290, doi: 10.1038/nbt.2831 [link]

Mosca R*, Céol A*, Stein A, Olivella R, Aloy P, 3did: a catalog of domain-based interactions of known three-dimensional structure, Nucleic Acids Research 2014, 42(1):D374-9, doi: 10.1093/nar/gkt887 [link]

Mosca R*, Pons T*, Céol A*, Valencia A, Aloy P, Towards a detailed atlas of protein-protein interactions, Current Opinion in Structural Biology 2013, 23, doi: 10.1016/j.sbi.2013.07.005 [link]

Duran-Frigola M*, Mosca R*, Aloy P, Structural Systems Pharmacology: the role of 3D structures in next generation drug development, Chemistry & Biology 2013, 20(5):674-684, doi: 10.1016/j.chembiol.2013.03.004 [link]

Quiles F, Fernández-Rodríguez J, Mosca R, Feliubadaló L, Tornero E, Brunet J, Blanco I, Capellá G, Pujana MA, Aloy P, Monteiro A, Lázaro C, Functional and Structural Analysis of C-Terminal BRCA1 Missense Variants, PLoS ONE 2013, 8(4): e61302, doi:10.1371/journal.pone.0061302 [link]

Mosca R, Céol A, Aloy P, Interactome3D: adding structural details to protein networks, Nature Methods 2013, 10(1):47-53, doi:10.1038/nmeth.2289 [link]

Mosca R, Pache RA, Aloy P, The role of structural disorder in the rewiring of protein interactions through evolution, Molecular & Cellular Proteomics 2012, doi: 10.1074/mcp.M111.014969 [link]

Stein A*, Mosca R*, Aloy P, Three-dimensional modeling of protein interactions and complexes is going 'omics, Current Opinion in Structural Biology 2011, doi: 10.1016/j.sbi.2011.01.005 [link]

Pujol A, Mosca R, Farrés J, Aloy P, Unveiling the role of network and systems biology in drug discovery, Trends in Pharmacological Sciences 2010, doi:10.1016/j.tips.2009.11.006 [link]

Mosca R, Pons C, Fernández-Recio J, Aloy P, Pushing Structural Information into the Yeast Interactome by High-Throughput Protein Docking Experiments, PLoS Comput Biol 2009 Vol. 5, No. 8, e1000490, doi:10.1371/journal.pcbi.1000490 [link] [Docking results]

Simonetta M, Manzoni R, Mosca R, Mapelli M, Massimiliano L, The Influence of Catalysis on Mad2 Activation Dynamics, PLoS Biology 2008, Vol. 7, No. 1, e10, doi:10.1371/journal.pbio.1000010 [link]

Mosca R, Schneider TR, RAPIDO: a web server for the alignment of protein structures in the presence of conformational changes, Nucleic Acids Research 2008, doi: 10.1093/nar/gkn197 [link]

Mosca R, Brannetti B, Schneider TR. Alignment of protein structures in the presence of domain motions, BMC Bioinformatics 2008, 9:352, doi:10.1186/1471-2105-9-352 [link]