Proteome-wide, Structure-Based Prediction of Protein-Protein Interactions/New Molecular Interactions Viewer1[OPEN]

A structure-based interactome for Arabidopsis and new community tools for accessing it and ∼2.8 million other interactions provides researchers with new opportunities for hypothesis generation. Determining the complete Arabidopsis (Arabidopsis thaliana) protein-protein interaction network is essential for understanding the functional organization of the proteome. Numerous small-scale studies and a couple of large-scale ones have elucidated a fraction of the estimated 300,000 binary protein-protein interactions in Arabidopsis. In this study, we provide evidence that a docking algorithm has the ability to identify real interactions using both experimentally determined and predicted protein structures. We ranked 0.91 million interactions generated by all possible pairwise combinations of 1,346 predicted structure models from an Arabidopsis predicted “structure-ome” and found a significant enrichment of real interactions for the top-ranking predicted interactions, as shown by cosubcellular enrichment analysis and yeast two-hybrid validation. Our success rate for computationally predicted, structure-based interactions was 63% of the success rate for published interactions naively tested using the yeast two-hybrid system and 2.7 times better than for randomly picked pairs of proteins. This study provides another perspective in interactome exploration and biological network reconstruction using protein structural information. We have made these interactions freely accessible through an improved Arabidopsis Interactions Viewer and have created community tools for accessing these and ∼2.8 million other protein-protein and protein-DNA interactions for hypothesis generation by researchers worldwide. The Arabidopsis Interactions Viewer is freely available at http://bar.utoronto.ca/interactions2/.

[1]  Nicholas J. Provart,et al.  An “Electronic Fluorescent Pictograph” Browser for Exploring and Analyzing Large-Scale Biological Data Sets , 2007, PloS one.

[2]  Sorina C. Popescu,et al.  Differential binding of calmodulin-related proteins to their targets revealed through high-density Arabidopsis protein microarrays , 2007, Proceedings of the National Academy of Sciences.

[3]  M. Bennett,et al.  Lateral root emergence in Arabidopsis is dependent on transcription factor LBD29 regulation of auxin influx carrier LAX3 , 2016, Development.

[4]  Kara Dolinski,et al.  The BioGRID interaction database: 2017 update , 2016, Nucleic Acids Res..

[5]  Ilya A Vakser,et al.  Protein-protein docking: from interaction to interactome. , 2014, Biophysical journal.

[6]  Alfonso Valencia,et al.  Towards the prediction of protein interaction partners using physical docking , 2011, Molecular systems biology.

[7]  Doreen Ware,et al.  Enhanced Y1H assays for Arabidopsis , 2011, Nature Methods.

[8]  C. Dominguez,et al.  HADDOCK: a protein-protein docking approach based on biochemical or biophysical information. , 2003, Journal of the American Chemical Society.

[9]  D. Ritchie,et al.  Protein docking using spherical polar Fourier correlations , 2000, Proteins.

[10]  F. Bischoff,et al.  Export of importin alpha from the nucleus is mediated by a specific nuclear transport factor. , 1997, Cell.

[11]  Julie M. Sahalie,et al.  An experimentally derived confidence score for binary protein-protein interactions , 2008, Nature Methods.

[12]  Gary D. Bader,et al.  Cytoscape.js: a graph theory library for visualisation and analysis , 2015, Bioinform..

[13]  Dmitrij Frishman,et al.  Negatome 2.0: a database of non-interacting proteins derived by literature mining, manual annotation and protein structure analysis , 2013, Nucleic Acids Res..

[14]  W. Shen,et al.  Histone H2A/H2B chaperones: from molecules to chromatin-based functions in plant growth and development. , 2015, The Plant journal : for cell and molecular biology.

[15]  Mathew G. Lewsey,et al.  Cistrome and Epicistrome Features Shape the Regulatory DNA Landscape , 2016, Cell.

[16]  R. Nussinov,et al.  Folding funnels, binding funnels, and protein function , 1999, Protein science : a publication of the Protein Society.

[17]  F. Bischoff,et al.  Export of Importin α from the Nucleus Is Mediated by a Specific Nuclear Transport Factor , 1997, Cell.

[18]  Jonathan D. G. Jones,et al.  Evidence for Network Evolution in an Arabidopsis Interactome Map , 2011, Science.

[19]  P. Shannon,et al.  Cytoscape: a software environment for integrated models of biomolecular interaction networks. , 2003, Genome research.

[20]  Andrej Sali,et al.  Comparative protein structure modeling as an optimization problem , 1997 .

[21]  Molly Megraw,et al.  Establishment of Expression in the SHORTROOT-SCARECROW Transcriptional Cascade through Opposing Activities of Both Activators and Repressors. , 2016, Developmental cell.

[22]  T. Richmond,et al.  Crystal structure of the nucleosome core particle at 2.8 Å resolution , 1997, Nature.

[23]  Ben Shneiderman,et al.  The eyes have it: a task by data type taxonomy for information visualizations , 1996, Proceedings 1996 IEEE Symposium on Visual Languages.

[24]  F. Thibaud-Nissen,et al.  Araport11: a complete reannotation of the Arabidopsis thaliana reference genome , 2016, bioRxiv.

[25]  Ian R. Castleden,et al.  SUBA3: a database for integrating experimentation and prediction to define the SUBcellular location of proteins in Arabidopsis , 2012, Nucleic Acids Res..

[26]  Juan Fernández-Recio,et al.  Pushing Structural Information into the Yeast Interactome by High-Throughput Protein Docking Experiments , 2009, PLoS Comput. Biol..

[27]  A G Murzin,et al.  SCOP: a structural classification of proteins database for the investigation of sequences and structures. , 1995, Journal of molecular biology.

[28]  Eric Bonnet,et al.  A Tandem Affinity Purification-based Technology Platform to Study the Cell Cycle Interactome in Arabidopsis thaliana*S , 2007, Molecular & Cellular Proteomics.

[29]  Peter Uetz,et al.  Exhaustive benchmarking of the yeast two-hybrid system , 2010, Nature Methods.

[30]  M. S. Mukhtar,et al.  Arabidopsis G-protein interactome reveals connections to cell wall carbohydrates and morphogenesis , 2011, Molecular systems biology.

[31]  Seung Y. Rhee,et al.  Uncovering Arabidopsis Membrane Protein Interactome Enriched in Transporters Using Mating-Based Split Ubiquitin Assays and Classification Models , 2012, Front. Plant Sci..

[32]  Rafael C. Jimenez,et al.  The IntAct molecular interaction database in 2012 , 2011, Nucleic Acids Res..

[33]  P. Bates,et al.  SwarmDock and the Use of Normal Modes in Protein-Protein Docking , 2010, International journal of molecular sciences.

[34]  D. Inzé,et al.  RALFL34 regulates formative cell divisions in Arabidopsis pericycle during lateral root initiation , 2016, Journal of experimental botany.

[35]  D. Kliebenstein,et al.  Promoter-Based Integration in Plant Defense Regulation1[W][OPEN] , 2014, Plant Physiology.

[36]  Erik S. Ferlanti,et al.  ePlant: Visualizing and Exploring Multiple Levels of Data for Hypothesis Generation in Plant Biology[OPEN] , 2017, Plant Cell.

[37]  S. Brady,et al.  Transcriptional Regulation of Arabidopsis Polycomb Repressive Complex 2 Coordinates Cell-Type Proliferation and Differentiation[OPEN] , 2016, Plant Cell.

[38]  A. Harvey Millar,et al.  A Predicted Interactome for Arabidopsis1[C][W][OA] , 2007, Plant Physiology.

[39]  M. S. Mukhtar,et al.  Independently Evolved Virulence Effectors Converge onto Hubs in a Plant Immune System Network , 2011, Science.

[40]  Michael J E Sternberg,et al.  The Phyre2 web portal for protein modeling, prediction and analysis , 2015, Nature Protocols.

[41]  Hiroshi Kimura,et al.  Regulation of RNA polymerase II activation by histone acetylation in single living cells , 2014, Nature.

[42]  M. Hochstrasser,et al.  Molecular organization of the 20S proteasome gene family from Arabidopsis thaliana. , 1998, Genetics.

[43]  Davide Heller,et al.  STRING v10: protein–protein interaction networks, integrated over the tree of life , 2014, Nucleic Acids Res..

[44]  E. Levy.  A simple definition of structural regions in proteins and its use in analyzing interface evolution. , 2010, Journal of molecular biology.

[45]  Roger D Kornberg,et al.  RNA polymerase II transcription: structure and mechanism. , 2013, Biochimica et biophysica acta.

[46]  Molly Megraw,et al.  A stele-enriched gene regulatory network in the Arabidopsis root , 2011, Molecular systems biology.

[47]  Gary D Bader,et al.  PSICQUIC and PSISCORE: accessing and scoring molecular interactions , 2011, Nature Methods.

[48]  Jason A. Corwin,et al.  An Arabidopsis Gene Regulatory Network for Secondary Cell Wall Synthesis , 2014, Nature.

[49]  Tom L. Blundell,et al.  Comprehensive, atomic-level characterization of structurally characterized protein-protein interactions: the PICCOLO database , 2011, BMC Bioinformatics.

[50]  Sergey Lyskov,et al.  The RosettaDock server for local protein–protein docking , 2008, Nucleic Acids Res..

[51]  Yoichiro Fukao,et al.  Protein-protein interactions in plants. , 2012, Plant & cell physiology.

[52]  S. Chen,et al.  The Arabidopsis Chaperone J3 Regulates the Plasma Membrane H+-ATPase through Interaction with the PKS5 Kinase[C][W] , 2010, Plant Cell.

[53]  Joshua S Yuan,et al.  Plant Protein-Protein Interaction Network and Interactome , 2010, Current genomics.

[54]  Juan Fernández-Recio,et al.  Cell biology: Brief encounters bolster contacts , 2006, Nature.

[55]  Z. Xiang,et al.  Advances in homology protein structure modeling. , 2006, Current protein & peptide science.

[56]  Zhiping Weng,et al.  Protein–protein docking benchmark version 4.0 , 2010, Proteins.

[57]  S. Rhee,et al.  MAPMAN: a user-driven tool to display genomics data sets onto diagrams of metabolic pathways and other biological processes. , 2004, The Plant journal : for cell and molecular biology.

[58]  S. Chen,et al.  The Arabidopsis Chaperone J3 Regulates the Plasma Membrane H+-ATPase through Interaction with the PKS5 Kinase[C][W] , 2010, Plant Cell.

[59]  F. Wilcoxon,et al.  Individual comparisons of grouped data by ranking methods. , 1946, Journal of economic entomology.

[60]  Ian R. Castleden,et al.  SUBAcon: a consensus algorithm for unifying the subcellular localization data of the Arabidopsis proteome , 2014, Bioinform..

[61]  Veena,et al.  Constitutive Expression Exposes Functional Redundancy between the Arabidopsis Histone H2A Gene HTA1 and Other H2A Gene Family Members[OA] , 2006, The Plant Cell Online.

[62]  R. Ozawa,et al.  A comprehensive two-hybrid analysis to explore the yeast protein interactome , 2001, Proceedings of the National Academy of Sciences of the United States of America.

[63]  B. Poovaiah,et al.  Arabidopsis chloroplast chaperonin 10 is a calmodulin-binding protein. , 2000, Biochemical and biophysical research communications.

[64]  R Core Team,et al.  R: A language and environment for statistical computing. , 2014 .

[65]  Elena Conti,et al.  Structural biology of nucleocytoplasmic transport. , 2007, Annual review of biochemistry.