Using HHsearch to tackle proteins of unknown function: A pilot study with PH domains. (9th October 2016)

• Record Type: Journal Article
• Authors: Fidler, David R.; Murphy, Sarah E.; Courtis, Katherine; Antonoudiou, Pantelis; El‐Tohamy, Rana; Ient, Jonathan; Levine, Timothy P.
• Is Part Of: Traffic. Volume 17:Number 11(2016)
• Page Start: 1214
• Page End: 1226
• Publication Date: 2016-10-09
• Subjects: GRAM domains -- Gyp7p -- pleckstrin homology (PH) domains -- profile‐profile search -- Saccharomyces cerevisiae -- secondary structure prediction -- structural bioinformatics -- TBC1D15 -- Vid27p, Vps13p -- YJL016W -- YJL181C -- YJR030C; Biological transport -- Periodicals; 571.6
• DOI: 10.1111/tra.12432
• Languages: English
• ISSNs: 1398-9219

Abstract

Abstract : Advances in membrane cell biology are hampered by the relatively high proportion of proteins with no known function. Such proteins are largely or entirely devoid of structurally significant domain annotations. Structural bioinformaticians have developed profile‐profile tools such as HHsearch (online version called HHpred), which can detect remote homologies that are missed by tools used to annotate databases. Here we have applied HHsearch to study a single structural fold in a single model organism as proof of principle. In the entire clan of protein domains sharing the pleckstrin homology domain fold in yeast, systematic application of HHsearch accurately identified known PH‐like domains. It also predicted 16 new domains in 13 yeast proteins many of which are implicated in intracellular traffic. One of these was Vps13p, where we confirmed the functional importance of the predicted PH‐like domain. Even though such predictions require considerable work to be corroborated, they are useful first steps. HHsearch should be applied more widely, particularly across entire proteomes of model organisms, to significantly improve database annotations. Abstract : HHsearch (available online as HHpred) is a powerful bioinformatics tool that examines the predicted 3D structure of a protein to detect remote protein homologies. We have applied HHsearch to study a single structural fold (PH and PH‐like domains) in a single model organism (yeast) as proof of principle. HHsearch detected known domains in yeast with 99% specificity as well 16 new PH‐like domains in 13 proteins. We corroborated the functional importance of 1 predicted domain in Vps13. Similar remote homology searches should be applied genome‐wide.