A reference map of the human binary protein interactome

Global insights into cellular organization and genome function require comprehensive understanding of the interactome networks that mediate genotype–phenotype relationships 1 , 2 . Here we present a human ‘all-by-all’ reference interactome map of human binary protein interactions, or ‘HuRI’. With approximately 53,000 protein–protein interactions, HuRI has approximately four times as many such interactions as there are high-quality curated interactions from small-scale studies. The integration of HuRI with genome 3 , transcriptome 4 and proteome 5 data enables cellular function to be studied within most physiological or pathological cellular contexts. We demonstrate the utility of HuRI in identifying the specific subcellular roles of protein–protein interactions. Inferred tissue-specific networks reveal general principles for the formation of cellular context-specific functions and elucidate potential molecular mechanisms that might underlie tissue-specific phenotypes of Mendelian diseases. HuRI is a systematic proteome-wide reference that links genomic variation to phenotypic outcomes. A human binary protein interactome map that includes around 53,000 protein–protein interactions involving more than 8,000 proteins provides a reference for the study of human cellular function in health and disease.

Patrick Aloy | Gary D. Bader | Yang Wang | Gary D Bader | Yu Xia | Soon Gang Choi | Luke Lambourne | Michael A. Calderwood | Frederick P. Roth | Yun Shen | Joseph N. Paulson | Thomas Rolland | Francisco J. Campos-Laborie | Janusz Rak | Murat Taşan | Xinping Yang | Andrew MacWilliams | Amélie Dricot | Benoit Charloteaux | Omer Basha | Esti Yeger-Lotem | Dae-Kyum Kim | István A. Kovács | Robert J. Weatheritt | Katja Luck | Roujia Li | Miquel Duran-Frigola | Joseph C. Mellor | Marinella Gebbia | Carles Pons | Suzanne Gaudet | Adriana San-Miguel | Mohamed Helmy | Kerstin Spirohn | Irma Lemmens | Sudharshan Rangarajan | Wenting Bian | Javier De Las Rivas | Jean-Claude Twizere | Tong Hao | Yves Jacob | Nishka Kishore | Jan Tavernier | David E. Hill | Gloria M. Sheynkman | Carl Pollis | Sadie Schlabach | Suet-Feung Chin | Mariana Babor | Marc Vidal | Eyal Simonovsky | Bridget E. Begg | Ruth Brignall | Tiziana Cafarelli | Dongsic Choi | Atina G. Coté | Meaghan Daley | Steven Deimling | Alice Desbuleux | Madeleine F. Hardy | Jennifer J. Knapp | Miles W. Mee | Aaron D. Richardson | Bridget Teeking | Anupama Yadav | Dawit Balcha | Christian Bowman-Colin | Claudia Colabella | Georges Coppin | Cassandra D’Amata | David De Ridder | Steffi De Rouck | Hanane Ennajdaoui | Florian Goebels | Liana Goehring | Anjali Gopal | Ghazal Haddad | Elodie Hatchi | Yoseph Kassa | Serena Landini | Natascha van Lieshout | Dylan Markey | John Rasla | Ashyad Rayhan | Dayag Sheykhkarimli | Alexander Tejeda | Vincent Tropepe | Jochen Weile | Quan Zhong | M. Vidal | S. Gaudet | M. Calderwood | A. Dricot | M. Tasan | P. Aloy | B. Charloteaux | S. Chin | Yu Xia | M. Gebbia | I. Lemmens | J. Tavernier | J. Twizere | Q. Zhong | Y. Jacob | T. Rolland | Yun Shen | Katja Luck | Kerstin Spirohn | Yang Wang | Carl Pollis | Sadie Schlabach | Dae-Kyum Kim | Nishka Kishore | Xinping Yang | Dawit Balcha | M. Hardy | John Rasla | Alexander O. Tejeda | G. Sheynkman | Esti Yeger-Lotem | J. Paulson | Jochen Weile | Jennifer J. Knapp | J. Mellor | Carles Pons | N. van Lieshout | Miquel Duran-Frigola | Steven J. Deimling | V. Tropepe | L. Lambourne | R. Brignall | T. Cafarelli | F. Campos-Laborie | D. Choi | Meaghan C. Daley | A. Desbuleux | Aaron D. Richardson | Bridget Teeking | Anupama Yadav | Mariana Babor | C. Bowman-Colin | Soon-gang Choi | Claudia Colabella | Georges Coppin | Cassandra D’Amata | D. de Ridder | Steffi de Rouck | Hanane Ennajdaoui | Florian Goebels | Liana J Goehring | Anjali Gopal | Ghazal Haddad | Elodie Hatchi | M. Helmy | Yoseph Kassa | Serena Landini | Roujia Li | D. Markey | Ashyad Rayhan | A. San-Miguel | Dayag Sheykhkarimli | Eyal Simonovsky | Y. Wang | J. Rak | Yu-ting Xia | F. Roth | A. MacWilliams | J. de Las Rivas | D. Hill | Sudharshan Rangarajan | Marc Vidal | Jan Tavernier | Omer Basha | Tong Hao | Wenting Bian | J. Rak | J De Las Rivas | S. Choi | Dongsic Choi | Amélie Dricot | Ruth Brignall | Christian Bowman-Colin | Yun A Shen | D. Hill | Alice Desbuleux | Gloria M. Sheynkman

[1]  Kerstin Menck,et al.  Syntenin mediates SRC function in exosomal cell-to-cell communication , 2017, Proceedings of the National Academy of Sciences.

[2]  A. Barabasi,et al.  Lethality and centrality in protein networks , 2001, Nature.

[3]  A. Barabasi,et al.  An empirical framework for binary interactome mapping , 2008, Nature Methods.

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

[5]  Marco Y. Hein,et al.  A Human Interactome in Three Quantitative Dimensions Organized by Stoichiometries and Abundances , 2015, Cell.

[6]  Hampapathalu Adimurthy Nagarajaram,et al.  Global versus local hubs in human protein-protein interaction network. , 2013, Journal of proteome research.

[7]  Steven A Carr,et al.  TMEM258 Is a Component of the Oligosaccharyltransferase Complex Controlling ER Stress and Intestinal Inflammation. , 2016, Cell reports.

[8]  James Y. Zou Analysis of protein-coding genetic variation in 60,706 humans , 2015, Nature.

[9]  Dmitri D. Pervouchine,et al.  The human transcriptome across tissues and individuals , 2015, Science.

[10]  Bridget E. Begg,et al.  A Proteome-Scale Map of the Human Interactome Network , 2014, Cell.

[11]  J. Gleeson,et al.  A Homozygous IER3IP1 Mutation Causes Microcephaly With Simplified Gyral Pattern, Epilepsy, and Permanent Neonatal Diabetes Syndrome (MEDS) , 2012, American journal of medical genetics. Part A.

[12]  D. Mccormick Sequence the Human Genome , 1986, Bio/Technology.

[13]  K. Umesono,et al.  LXR, a nuclear receptor that defines a distinct retinoid response pathway. , 1995, Genes & development.

[14]  Keith W. Caldecott,et al.  Impact of PNKP mutations associated with microcephaly, seizures and developmental delay on enzyme activity and DNA strand break repair , 2012, Nucleic acids research.

[15]  A. Barabasi,et al.  High-Quality Binary Protein Interaction Map of the Yeast Interactome Network , 2008, Science.

[16]  Lei Yang,et al.  Comparative analysis of housekeeping and tissue-selective genes in human based on network topologies and biological properties , 2016, Molecular Genetics and Genomics.

[17]  István A. Kovács,et al.  Widespread Macromolecular Interaction Perturbations in Human Genetic Disorders , 2015, Cell.

[18]  S. L. Wong,et al.  Towards a proteome-scale map of the human protein–protein interaction network , 2005, Nature.

[19]  Alicia Llorente,et al.  Current knowledge on exosome biogenesis and release , 2017, Cellular and Molecular Life Sciences.

[20]  François Schiettecatte,et al.  OMIM.org: Online Mendelian Inheritance in Man (OMIM®), an online catalog of human genes and genetic disorders , 2014, Nucleic Acids Res..

[21]  Nicolas Thierry-Mieg,et al.  New insights into protein-protein interaction data lead to increased estimates of the S. cerevisiae interactome size , 2010, BMC Bioinformatics.

[22]  International Human Genome Sequencing Consortium Initial sequencing and analysis of the human genome , 2001, Nature.

[23]  L. Castagnoli,et al.  mentha: a resource for browsing integrated protein-interaction networks , 2013, Nature Methods.

[24]  Ilan Y. Smoly,et al.  Comparative Analysis of Human Tissue Interactomes Reveals Factors Leading to Tissue-Specific Manifestation of Hereditary Diseases , 2014, PLoS Comput. Biol..

[25]  Ben Lehner,et al.  Tissue specificity and the human protein interaction network , 2009, Molecular systems biology.

[26]  Cesare Furlanello,et al.  A promoter-level mammalian expression atlas , 2015 .

[27]  P. Vidalain,et al.  Benchmarking a luciferase complementation assay for detecting protein complexes , 2011, Nature Methods.

[28]  Anastasia Baryshnikova,et al.  Systematic Functional Annotation and Visualization of Biological Networks , 2016, bioRxiv.

[29]  Claude Gazin,et al.  TRIM37 is a new histone H2A ubiquitin ligase and breast cancer oncoprotein , 2014, Nature.

[30]  M. Madan Babu,et al.  A million peptide motifs for the molecular biologist. , 2014, Molecular cell.

[31]  A. Barabasi,et al.  Interactome Networks and Human Disease , 2011, Cell.

[32]  Isidro Ferrer,et al.  New cardiac and skeletal protein aggregate myopathy associated with combined MuRF1 and MuRF3 mutations. , 2015, Human molecular genetics.

[33]  Katherine S. Pollard,et al.  ProteinHistorian: Tools for the Comparative Analysis of Eukaryote Protein Origin , 2012, PLoS Comput. Biol..

[34]  John Quackenbush,et al.  Tissue-aware RNA-Seq processing and normalization for heterogeneous and sparse data , 2016, BMC Bioinformatics.

[35]  Devin K. Schweppe,et al.  Architecture of the human interactome defines protein communities and disease networks , 2017, Nature.

[36]  Chunlei Liu,et al.  ClinVar: improving access to variant interpretations and supporting evidence , 2017, Nucleic Acids Res..

[37]  Gloria M. Sheynkman,et al.  Widespread Expansion of Protein Interaction Capabilities by Alternative Splicing , 2016, Cell.

[38]  T. Ideker,et al.  Exome Sequencing Links Corticospinal Motor Neuron Disease to Common Neurodegenerative Disorders , 2014, Science.

[39]  Philippe Kastner,et al.  Purification, cloning, and RXR identity of the HeLa cell factor with which RAR or TR heterodimerizes to bind target sequences efficiently , 1992, Cell.

[40]  P. Kam,et al.  : 4 , 1898, You Can Cross the Massacre on Foot.

[41]  Albert-László Barabási,et al.  Network-based prediction of protein interactions , 2018, Nature Communications.

[42]  Fabian J Theis,et al.  The Human Cell Atlas , 2017, bioRxiv.

[43]  Aviad Tsherniak,et al.  Interrogation of Mammalian Protein Complex Structure, Function, and Membership Using Genome-Scale Fitness Screens. , 2018, Cell systems.

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

[45]  Greg W. Clark,et al.  Panorama of ancient metazoan macromolecular complexes , 2015, Nature.

[46]  Jan Tavernier,et al.  Design and application of a cytokine-receptor-based interaction trap , 2001, Nature Cell Biology.

[47]  Soon Gang Choi,et al.  Maximizing binary interactome mapping with a minimal number of assays , 2019, Nature Communications.

[48]  P. Aloy,et al.  Interactome3D: adding structural details to protein networks , 2013, Nature Methods.

[49]  Yasunori Yamamoto,et al.  Arl6IP1 has the ability to shape the mammalian ER membrane in a reticulon-like fashion. , 2014, The Biochemical journal.

[50]  Antonella Bongiovanni,et al.  EVpedia: a community web portal for extracellular vesicles research , 2015, Bioinform..