Using HHsearch to tackle proteins of unknown function: A pilot study with PH domains.
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.
Department of Cell Biology, UCL Institute of Ophthalmology, London, UK.
David R
DR
Fidler
Department of Cell Biology, UCL Institute of Ophthalmology, London, UK.
Sarah E
SE
Murphy
Department of Cell Biology, UCL Institute of Ophthalmology, London, UK.
Katherine
K
Courtis
Department of Cell Biology, UCL Institute of Ophthalmology, London, UK.
Pantelis
P
Antonoudiou
Department of Cell Biology, UCL Institute of Ophthalmology, London, UK.
Rana
R
El-Tohamy
Department of Cell Biology, UCL Institute of Ophthalmology, London, UK.
Jonathan
J
Ient
Department of Cell Biology, UCL Institute of Ophthalmology, London, UK. tim.levine@ucl.ac.uk.
Timothy P
TP
Levine
D019295:Computational Biology / Q000379:methods; D030562:Databases, Protein; D008565:Membrane Proteins / Q000737:chemistry*; D010865:Pilot Projects; D000070539:Pleckstrin Homology Domains; D017433:Protein Structure, Secondary; D029701:Saccharomyces cerevisiae Proteins / Q000737:chemistry*; D017386:Sequence Homology, Amino Acid; D012984:Software
D008565:Membrane Proteins; D029701:Saccharomyces cerevisiae Proteins

GRAM domains; 
Saccharomyces cerevisiae
; 
TBC1D15
; 
YJL016W
; 
YJL181C
; 
YJR030C
; Gyp7p; Vid27p, Vps13p; pleckstrin homology (PH) domains; profile-profile search; secondary structure prediction; structural bioinformatics