Shaping the future of interactome networks

A report of the third Interactome Networks Conference, Hinxton, UK, 29 August-1 September 2007

Contextual Specificity in Peptide-Mediated Protein Interactions

Most biological processes are regulated through complex networks of transient protein interactions where a globular domain in one protein recognizes a linear peptide from another, creating a relatively small contact interface. Although sufficient to ensure binding, these linear motifs alone are usually too short to achieve the high specificity observed, and additional contacts are often encoded in the residues surrounding the motif (i.e. the context). Here, we systematically identified all instances of peptide-mediated protein interactions of known three-dimensional structure and used them to investigate the individual contribution of motif and context to the global binding energy. We found that, on average, the context is responsible for roughly 20% of the binding and plays a crucial role in determining interaction specificity, by either improving the affinity with the native partner or impeding non-native interactions. We also studied and quantified the topological and energetic variability of interaction interfaces, finding a much higher heterogeneity in the context residues than in the consensus binding motifs. Our analysis partially reveals the molecular mechanisms responsible for the dynamic nature of peptide-mediated interactions, and suggests a global evolutionary mechanism to maximise the binding specificity. Finally, we investigated the viability of non-native interactions and highlight cases of potential cross-reaction that might compensate for individual protein failure and establish backup circuits to increase the robustness of cell networks

Exploiting gene deletion fitness effects in yeast to understand the modular architecture of protein complexes under different growth conditions

RIGHTS : This article is licensed under the BioMed Central licence at http://www.biomedcentral.com/about/license which is similar to the 'Creative Commons Attribution Licence'. In brief you may : copy, distribute, and display the work; make derivative works; or make commercial use of the work - under the following conditions: the original author must be given credit; for any reuse or distribution, it must be made clear to others what the license terms of this work are.Abstract Background Understanding how individual genes contribute towards the fitness of an organism is a fundamental problem in biology. Although recent genome-wide screens have generated abundant data on quantitative fitness for single gene knockouts, very few studies have systematically integrated other types of biological information to understand how and why deletion of specific genes give rise to a particular fitness effect. In this study, we combine quantitative fitness data for single gene knock-outs in yeast with large-scale interaction discovery experiments to understand the effect of gene deletion on the modular architecture of protein complexes, under different growth conditions. Results Our analysis reveals that genes in complexes show more severe fitness effects upon deletion than other genes but, in contrast to what has been observed in binary protein-protein interaction networks, we find that this is not related to the number of complexes in which they are present. We also find that, in general, the core and attachment components of protein complexes are equally important for the complex machinery to function. However, when quantifying the importance of core and attachments in single complex variations, or isoforms, we observe that this global trend originates from either the core or the attachment components being more important for strain fitness, both being equally important or both being dispensable. Finally, our study reveals that different isoforms of a complex can exhibit distinct fitness patterns across growth conditions. Conclusion This study presents a powerful approach to unveil the molecular basis for various complex phenotypic profiles observed in gene deletion experiments. It also highlights some interesting cases of potential functional compensation between protein paralogues and suggests a new piece to fit into the histone-code puzzle.Published versio

3did: interacting protein domains of known three-dimensional structure

The database of 3D Interacting Domains (3did) is a collection of domain–domain interactions in proteins for which high-resolution three-dimensional structures are known. 3did exploits structural information to provide critical molecular details necessary for understanding how interactions occur. It also offers an overview of how similar in structure are interactions between different members of the same protein family. The database also contains Gene Ontology-based functional annotations and interactions between yeast proteins from large-scale interaction discovery studies. A web-based tool to query 3did is available at http://3did.embl.de

A chemo-centric view of human health and disease

Efforts to compile the phenotypic effects of drugs and environmental chemicals offer the opportunity to adopt a chemo-centric view of human health that does not require detailed mechanistic information. Here we consider thousands of chemicals and analyse the relationship of their structures with adverse and therapeutic responses. Our study includes molecules related to the aetiology of 934 health-threatening conditions and used to treat 835 diseases. We first identify chemical moieties that could be independently associated with each phenotypic effect. Using these fragments, we build accurate predictors for approximately 400 clinical phenotypes, finding many privileged and liable structures. Finally, we connect two diseases if they relate to similar chemical structures. The resulting networks of human conditions are able to predict disease comorbidities, as well as identifying potential drug side effects and opportunities for drug repositioning, and show a remarkable coincidence with clinical observations

Pushing Structural Information into the Yeast Interactome by High-Throughput Protein Docking Experiments

The last several years have seen the consolidation of high-throughput proteomics initiatives to identify and characterize protein interactions and macromolecular complexes in model organisms. In particular, more that 10,000 high-confidence protein-protein interactions have been described between the roughly 6,000 proteins encoded in the budding yeast genome (Saccharomyces cerevisiae). However, unfortunately, high-resolution three-dimensional structures are only available for less than one hundred of these interacting pairs. Here, we expand this structural information on yeast protein interactions by running the first-ever high-throughput docking experiment with some of the best state-of-the-art methodologies, according to our benchmarks. To increase the coverage of the interaction space, we also explore the possibility of using homology models of varying quality in the docking experiments, instead of experimental structures, and assess how it would affect the global performance of the methods. In total, we have applied the docking procedure to 217 experimental structures and 1,023 homology models, providing putative structural models for over 3,000 protein-protein interactions in the yeast interactome. Finally, we analyze in detail the structural models obtained for the interaction between SAM1-anthranilate synthase complex and the MET30-RNA polymerase III to illustrate how our predictions can be straightforwardly used by the scientific community. The results of our experiment will be integrated into the general 3D-Repertoire pipeline, a European initiative to solve the structures of as many as possible protein complexes in yeast at the best possible resolution. All docking results are available at http://gatealoy.pcb.ub.es/HT_docking/

Batch enrichment of anammox bacteria and study of the underlying microbial community dynamics

The anaerobic ammonium oxidation (anammox) consists on the biological conversion of ammonium (NH4+) into dinitrogen gas under absence of oxygen. Nitrite (NO2-) is a substrate of the anammox reaction, but also an inhibitor at high concentrations. This study investigates the effect of nitrite on the microbial community during the batch enrichment of anammox sludge. Six inoculums collected from different environments were enriched after a conditioning pretreatment and under controlled conditions during 4 months. Concerning the mineral medium used, two different nitrite supply strategies were applied; i.e., (i) initially low concentration at 25 mg NO2-–N/L and progressive increase to 150 mg NO2-–N/L, and (ii) constant high concentration at 150 mg NO2-–N/L. All tested inoculums developed anammox activity but only when the enrichment was started at low nitrite concentration. In such case, the specific ammonium conversion rates finally obtained ranged from 21 ±1 to 118 ±1 mg NH4+–N/g VS/d (VS, volatile solids). Abundance of the functional gene encoding for the enzyme hydrazine oxidoreductase (hzo) was assessed using the real-time quantitative polymerase chain reaction (q-PCR) showing positive correlation with the anammox activity finally reported. In addition, high-throughput DNA sequencing helped to elucidate the underlying microbial community dynamics. The raw inoculum source, the conditioning pretreatment, and the cultivation conditions applied were jointly determinants of the final microbial community structure of the enrichments despite a clear convergence at the end of the experimental period. On the other hand, the cultivation conditions alone determined the selection of anammox species belonging to the genus Candidatus Brocadia.Postprint (updated version

Evaluation of Albumin, Zinc and Vitamin C in Surgical Wound Patients

The serum albumin, zinc and vitamin C statuses of surgical wound patients attending General Hospital Owerri, Nigeria were investigated to determine whether or not the serum levels of these elements were normal. One hundred surgical wound patients age 20-40 years were selected. One hundred normal subjects age 20-40 years were used as control. The levels of albumin, zinc and vitamin C were significantly decreased in surgical wound patients, when compared with the control (p<0.05). The result suggests, but not conclusively, that supplementation of surgical wound patients, with food and drug containing albumin, zinc and vitamin C might be helpful, particularly for the healing f surgical wounds