Protease-inhibitor interaction predictions: Lessons on the complexity of protein-protein interactions
hdl:11272/10472
Version: 4 – Released: Mon Apr 03 12:09:04 PDT 2017
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TitleProtease-inhibitor interaction predictions: Lessons on the complexity of protein-protein interactions
Study Global IDhdl:11272/10472
AuthorsFortelny, Nikolaus (MSL, UBC); Butler, Georgina (Centre for Blood Research, UBC); Overall, Christopher (Centre for Blood Research, UBC); Pavlidis, Paul (MSL, UBC)
ProducerUniversity of British Columbia (UBC); Michael Smith Laboratories (MSL)
Production Date2017
Production PlaceVancouver, BC
Software R
Funding AgencyNIH, CIHR, CFI
DistributorUniversity of British Columbia (UBC)
DepositorSanja Rogic
Deposit DateMarch 30, 2017
Original Dataverse
Description and Scope
Description

Protein interactions shape proteome function and thus biology. Identification of protein interactions is a major goal in molecular biology, but biochemical methods, although improving, remain limited in coverage and accuracy. Whereas computational predictions can guide biochemical experiments, low validation rates of predictions remain a major limitation. Here, we investigated computational methods in the prediction of a specific type of interaction, the inhibitory interactions between proteases and their inhibitors. Proteases generate thousands of proteoforms that dynamically shape the functional state of proteomes. Despite the important regulatory role of proteases, knowledge of their inhibitors remains largely incomplete with the vast majority of proteases lacking an annotated inhibitor. To link inhibitors to their target proteases on a large scale, we applied computational methods to predict inhibitory interactions between proteases and their inhibitors based on complementary data including coexpression, phylogenetic similarity, structural information, co-annotation, and colocalization, and also surveyed general protein interaction networks for potential inhibitory interactions. In testing nine predicted interactions biochemically, we validated the inhibition of kallikrein 5 by serpin B12. Despite the use of a wide array of complementary data, we found a high false positive rate of computational predictions in biochemical follow-up. Based on a protease-specific definition of true negatives derived from the biochemical classification of proteases and inhibitors, we analyzed prediction accuracy of individual features. Thereby we identified feature-specific limitations, which also affected general protein interaction prediction methods. Interestingly, proteases were often not coexpressed with most of their functional inhibitors, contrary to what is commonly assumed and extrapolated predominantly from cell culture experiments. Predictions of inhibitory interactions were indeed more challenging than predictions of non-proteolytic and non-inhibitory interactions. In summary, we describe a novel and well-defined but difficult protein interaction prediction task, and thereby highlight limitations of computational interaction prediction methods.

Description DateMarch, 2017
Keywordsproteases; protein-protein interaction; protease-inhibitor interaction; computational prediction
Topic ClassificationOpen (Open Access Tag)
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Number of Files 1
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RestrictionsCreative Commons Licence
This work is licensed under a Creative Commons Attribution 4.0 International License.
ContactPaul Pavlidis, paul@msl.ubc.ca
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"Protease-inhibitor interaction predictions: Lessons on the complexity of protein-protein interactions", hdl:11272/10472