FACT: Functional annotation transfer between proteins with similar feature architectures

Abstract

BackgroundThe increasing number of sequenced genomes provides the basis for exploring the genetic and functional diversity within the tree of life. Only a tiny fraction of the encoded proteins undergoes a thorough experimental characterization. For the remainder, bioinformatics annotation tools are the only means to infer their function. Exploiting significant sequence similarities to already characterized proteins, commonly taken as evidence for homology, is the prevalent method to deduce functional equivalence. Such methods fail when homologs are too diverged, or when they have assumed a different function. Finally, due to convergent evolution, functional equivalence is not necessarily linked to common ancestry. Therefore complementary approaches are required to identify functional equivalents.ResultsWe present the Feature Architecture Comparison Tool http://www.cibiv.at/FACT to search for functionally equivalent proteins. FACT uses the similarity between feature architectures of two proteins, i.e., the arrangements of functional domains, secondary structure elements and compositional properties, as a proxy for their functional equivalence. A scoring function measures feature architecture similarities, which enables searching for functional equivalents in entire proteomes. Our evaluation of 9,570 EC classified enzymes revealed that FACT, using the full feature, set outperformed the existing architecture-based approaches by identifying significantly more functional equivalents as highest scoring proteins. We show that FACT can identify functional equivalents that share no significant sequence similarity. However, when the highest scoring protein of FACT is also the protein with the highest local sequence similarity, it is in 99% of the cases functionally equivalent to the query. We demonstrate the versatility of FACT by identifying a missing link in the yeast glutathione metabolism and also by searching for the human GolgA5 equivalent in Trypanosoma brucei.ConclusionsFACT facilitates a quick and sensitive search for functionally equivalent proteins in entire proteomes. FACT is complementary to approaches using sequence similarity to identify proteins with the same function. Thus, FACT is particularly useful when functional equivalents need to be identified in evolutionarily distant species, or when functional equivalents are not homologous. The most reliable annotation transfers, however, are achieved when feature architecture similarity and sequence similarity are jointly taken into account.

Mus81 nuclease and Sgs1 helicase are essential for meiotic recombination in a protist lacking a synaptonemal complex

“…BLAST searches for protein homologs to budding yeast Yen1 and its human ortholog GEN1 both produced TTHERM_00670390p as the first hit with limited local similarities. Moreover, the comparison of protein domains using the Feature Architecture Comparison Tool [FACT; http://fact.cibiv.univie.ac.at/index.php; (46)] revealed that Tetrahymena TTHERM_00670390p shares with Yen1 and GEN1 a similar arrangement of XPGN and XPGI regions. This makes TTHERM_00670390p a possible Yen1/GEN1 candidate.…”

NAD+ biosynthesis and salvage – a phylogenetic perspective

“…The results of the meme / mast mapping and interpro queries for the 64 enzymes are summarized in Table S3. Such a combination of sequence similarity and feature architecture is supposed to perform best for a reliable functional annotation transfer [38]. On the basis of manual inspection, we found that this approach performs very well in excluding false‐positives.…”

The Tetrahymena meiotic chromosome bouquet is organized by centromeres and promotes interhomolog recombination

“…However, we failed to detect any. Since the sequence conservation of telomere-associated proteins is generally poor (Linger and Price, 2009), we also compared protein domains using the Feature Architecture Comparison Tool (FACT; http:// fact.cibiv.univie.ac.at; Koestler et al, 2010). However, this search also produced only hits with a distant similarity to known telomere-associated proteins.…”