Analysis of the protein domain and domain architecture content in fungi and its application in the search of new antifungal targets

Over the past several years fungal infections have shown an increasing incidence in the susceptible population, and caused high mortality rates. In parallel, multi-resistant fungi are emerging in human infections. Therefore, the identification of new potential antifungal targets is a priority. The first task of this study was to analyse the protein domain and domain architecture content of the 137 fungal proteomes (corresponding to 111 species) available in UniProtKB (UniProt KnowledgeBase) by January 2013. The resulting list of core and exclusive domain and domain architectures is provided in this paper. It delineates the different levels of fungal taxonomic classification: phylum, subphylum, order, genus and species. The analysis highlighted Aspergillus as the most diverse genus in terms of exclusive domain content. In addition, we also investigated which domains could be considered promiscuous in the different organisms. As an application of this analysis, we explored three different ways to detect potential targets for antifungal drugs. First, we compared the domain and domain architecture content of the human and fungal proteomes, and identified those domains and domain architectures only present in fungi. Secondly, we looked for information regarding fungal pathways in public repositories, where proteins containing promiscuous domains could be involved. Three pathways were identified as a result: lovastatin biosynthesis, xylan degradation and biosynthesis of siroheme. Finally, we classified a subset of the studied fungi in five groups depending on their occurrence in clinical samples. We then looked for exclusive domains in the groups that were more relevant clinically and determined which of them had the potential to bind small molecules. Overall, this study provides a comprehensive analysis of the available fungal proteomes and shows three approaches that can be used as a first step in the detection of new antifungal targets.This work was funded by the project ‘PROBIOIFI’ (Spanish Ministry of Economy and Competitiveness, grant number EIC-EMBL-2011-0091, http://www.mineco.gob.es/portal/site/mineco/). JAV is funded by the Wellcome Trust [grants numbers WT085949MA and WT101477MA] (http://www.wellcome.ac.uk/) and the EU FP7 project ‘ProteomeXchange’ [grant number 260558]. AAI has a research contract from the Spanish Network for Research on Infectious Diseases (REIPI RD06/0008), supported by the Plan Nacional de I+D+i 2008–2011 and the Instituto de Salud Carlos III, Subdirección General de Redes y Centros de Investigación Cooperativa, Ministerio de Economía y Competitividad, and the Spanish Network for Research on Infectious Diseases (REIPI RD12/0015) - co-financed by the European development regional Fund “A Way to Achieve Europe” ERDF. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.S