ArticleNature biotechnology2025
A structurally informed human protein-protein interactome reveals proteome-wide perturbations caused by disease mutations.
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Article in Nature biotechnology, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 32 papers.
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32citing papers in PubMed
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32 citing papers in PubMed.
- Variant characterization in the intrinsically disordered human proteome.Nature structural & molecular biology · 2026Article
- Human genetics across levels of biological organization.Nature reviews. Genetics · 2026Review
- Allostery is a widespread cause of loss-of-function variant pathogenicity.Nature communications · 2026Article
- Generalist biological artificial intelligence in modeling the language of life.Nature biotechnology · 2026Review
- eSIG-Net: an interaction language model that decodes the protein code of single mutations.Nature methods · 2026Article
- CBFB mutations predict endocrine therapy benefit in estrogen receptor-positive breast cancer.medRxiv : the preprint server for health sciences · 2026Article
- Integrative network analysis reveals organizational principles of the endocannabinoid system.Journal of cannabis research · 2026Article
- Out-of-distribution generalization enhances protein function annotation for low-homology sequences.Briefings in bioinformatics · 2026Article
- Targeting protein protein interactions and their modulators to enable new therapeutic strategies for human diseases.NPJ systems biology and applications · 2026Review
- Several plant self-incompatibility systems may be controlled by atypical receptor-ligand interactions.The Plant journal : for cell and molecular biology · 2026Review
- eSIG-Net: Accurate prediction of single-mutation induced perturbations on protein interactions using a language model.bioRxiv : the preprint server for biology · 2026Article
- Interactome mapping in human excitatory neurons reveals novel risk genes and pathways in Alzheimer's disease.bioRxiv : the preprint server for biology · 2026Article
- Accurate Identification of Protein Binding Sites for All Drug Modalities Using ALLSites.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2026Article
- MOKCa-3D database: functional and structural analysis of missense mutations in cancer.Database : the journal of biological databases and curation · 2026Article
- Calibrated Variant Effect Prediction at the Residue Level Using Conditional Score Distributions.bioRxiv : the preprint server for biology · 2025Article
- Credible inferences in microbiome research: ensuring rigour, reproducibility and relevance in the era of AI.Nature reviews. Gastroenterology & hepatology · 2025Review
- Hydrogen-Deuterium Exchange Mass Spectrometry for Molecular Glue Characterization.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2025Article
- Predicting protein-protein interactions in the human proteome.Science (New York, N.Y.) · 2025Article
- Hub Occupancy by Competitively Interacting Proteins Obeys a Simple Queuing Law.The journal of physical chemistry. B · 2025Article
- Learning Universal Representations of Intermolecular Interactions with ATOMICA.bioRxiv : the preprint server for biology · 2025Article
Corrections and comments
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Authors and funding
14 authors.
Dapeng Xiong *Department of Computational Biology, Cornell University, Ithaca, NY, USA.
Yunguang Qiu *Cleveland Clinic Genome Center, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, USA.ORCID http://orcid.org/0000-0002-5094-0936
Junfei Zhao *Department of Systems Biology, Herbert Irving Comprehensive Center, Columbia University, New York, NY, USA.
Yadi Zhou *Cleveland Clinic Genome Center, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, USA.
Dongjin Lee *Department of Computational Biology, Cornell University, Ithaca, NY, USA.
Shobhita GuptaWeill Institute for Cell and Molecular Biology, Cornell University, Ithaca, NY, USA.
Mateo TorresDepartment of Computational Biology, Cornell University, Ithaca, NY, USA.ORCID http://orcid.org/0000-0002-9796-1742
Weiqiang LuShanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, Shanghai, China.ORCID http://orcid.org/0000-0003-1349-6597
Siqi LiangDepartment of Computational Biology, Cornell University, Ithaca, NY, USA.ORCID http://orcid.org/0000-0002-6433-5964
Jin Joo KangDepartment of Computational Biology, Cornell University, Ithaca, NY, USA.
Charis EngCleveland Clinic Genome Center, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, USA.ORCID http://orcid.org/0000-0002-3693-5145
Joseph LoscalzoChanning Division of Network Medicine, Division of Cardiovascular Medicine, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.ORCID http://orcid.org/0000-0002-1153-8047
Feixiong ChengCleveland Clinic Genome Center, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, USA. chengf@ccf.org.ORCID http://orcid.org/0000-0002-1736-2847
Haiyuan YuDepartment of Computational Biology, Cornell University, Ithaca, NY, USA. haiyuan.yu@cornell.edu.ORCID http://orcid.org/0000-0001-7597-6049
Funding
Boston Biomedical Innovation CenterU54HL119145 · NHLBI · BRIGHAM AND WOMEN'S HOSPITAL · PI GOLAN, DAVID E., LOSCALZO, JOSEPH · 2013 to 2021
$18.8MStructure, Function, and Dynamics of Macro-molecular Complexes that Execute and Regulate Genome FunctionRM1GM139738 · NIGMS · CORNELL UNIVERSITY · PI Thomas George Wade Graham, Steven Zvi Josefowicz · 2021 to 2026
$14.4MEndophenotype Network-based Approaches to Prediction and Population-based Validation of In Silico Drug Repurposing for Alzheimer's DiseaseR01AG066707 · NIA · CLEVELAND CLINIC LERNER COM-CWRU · PI Feixiong Cheng · 2020 to 2026
$4.9ML-2-Hydroxyglutarate and Metabolic Remodeling in HypoxiaR01HL155107 · NHLBI · BRIGHAM AND WOMEN'S HOSPITAL · PI Joseph Loscalzo · 2021 to 2026
$4.1MTREM2 Genotype-Informed Drug Repurposing and Combination Therapy Design for Alzheimers DiseaseR01AG076448 · NIA · CLEVELAND CLINIC LERNER COM-CWRU · PI Feixiong Cheng, Li Gan · 2022 to 2026
$4.0MAlzheimer's MultiOme Data Repurposing: Artificial Intelligence, Network Medicine, and Therapeutics DiscoveryU01AG073323 · NIA · CLEVELAND CLINIC LERNER COM-CWRU · PI BEKRIS, LYNN, CHENG, FEIXIONG · 2021 to 2025
$4.0MIntegrated high-throughput functional assays to identify ulcerative colitis causal risk variantsR01DK115398 · NIDDK · CORNELL UNIVERSITY · PI KLEIN, ROBERT J., YU, HAIYUAN · 2018 to 2022
$3.3MBranched-chain Keto-acids and Aerobic Glycolysis in Vascular Smooth Muscle CellsR01HL166137 · NHLBI · BRIGHAM AND WOMEN'S HOSPITAL · PI Joseph Loscalzo · 2023 to 2026
$2.8MInterface-resolution domain-domain interactome map of the yeast complexomeR01GM130885 · NIGMS · DANA-FARBER CANCER INST · PI VIDAL, MARC · 2019 to 2022
$2.7MQuantifying molecular consequences of human missense variants with large-scale interactome perturbation studiesR01GM125639 · NIGMS · CORNELL UNIVERSITY · PI ALEXOV, EMIL GEORGIEV, CLARK, ANDREW G · 2018 to 2021
$2.6MAlzheimer's Disease and Related Dementia-like Sequelae of SARS-CoV-2 Infection: Virus-Host Interactome, Neuropathobiology, and Drug RepurposingRF1AG082211 · NIA · CLEVELAND CLINIC LERNER COM-CWRU · PI CHENG, FEIXIONG, PIEPER, ANDREW A · 2023 to 2023
$2.4MCharacterize neuronal and glial cell-specific vulnerability to proteinopathies in Alzheimer's disease using multimodal single-nuclei genomic and epigenomic approachesR01AG082118 · NIA · CLEVELAND CLINIC LERNER COM-CWRU · PI BONAKDARPOUR, BORNA, CHENG, FEIXIONG · 2023 to 2025
$2.4MAmerican Heart Association (American Heart Association, Inc.) 24MERIT1185447American Heart Association (American Heart Association, Inc.) AHA957729American Heart Association-American Stroke Association 957729NCI NIH HHS U01 CA294154NHLBI NIH HHS R01 HL155096NHLBI NIH HHS R01 HL155107NHLBI NIH HHS U54 HL119145NIA NIH HHS R01 AG066707NIA NIH HHS R01 AG076448NIA NIH HHS R01 AG082118NIA NIH HHS R01 AG084250NIA NIH HHS R21 AG083003NIA NIH HHS R56 AG074001NIA NIH HHS RF1 AG082211NIA NIH HHS U01 AG073323NIDDK NIH HHS R01 DK115398NIGMS NIH HHS R01 GM124559NIGMS NIH HHS R01 GM125639NIGMS NIH HHS R01 GM130885NIGMS NIH HHS RM1 GM139738NINDS NIH HHS RF1 NS133812U.S. Department of Health & Human Services | NIH | National Heart, Lung, and Blood Institute (NHLBI) R01HL155096U.S. Department of Health & Human Services | NIH | National Heart, Lung, and Blood Institute (NHLBI) R01HL155107U.S. Department of Health & Human Services | NIH | National Heart, Lung, and Blood Institute (NHLBI) R01HL166137U.S. Department of Health & Human Services | NIH | National Heart, Lung, and Blood Institute (NHLBI) U54HL119145U.S. Department of Health & Human Services | NIH | National Human Genome Research Institute (NHGRI) U01HG007691U.S. Department of Health & Human Services | NIH | National Institute of Diabetes and Digestive and Kidney Diseases (National Institute of Diabetes & Digestive & Kidney Diseases) R01DK115398U.S. Department of Health & Human Services | NIH | National Institute of General Medical Sciences (NIGMS) R01GM124559U.S. Department of Health & Human Services | NIH | National Institute of General Medical Sciences (NIGMS) R01GM125639U.S. Department of Health & Human Services | NIH | National Institute of General Medical Sciences (NIGMS) R01GM130885U.S. Department of Health & Human Services | NIH | National Institute of General Medical Sciences (NIGMS) RM1GM139738U.S. Department of Health & Human Services | NIH | National Institute of Neurological Disorders and Stroke (NINDS) RF1NS133812U.S. Department of Health & Human Services | NIH | National Institute on Aging (U.S. National Institute on Aging) R01AG066707U.S. Department of Health & Human Services | NIH | National Institute on Aging (U.S. National Institute on Aging) R01AG076448U.S. Department of Health & Human Services | NIH | National Institute on Aging (U.S. National Institute on Aging) R01AG082118U.S. Department of Health & Human Services | NIH | National Institute on Aging (U.S. National Institute on Aging) R01AG084250U.S. Department of Health & Human Services | NIH | National Institute on Aging (U.S. National Institute on Aging) R21AG083003U.S. Department of Health & Human Services | NIH | National Institute on Aging (U.S. National Institute on Aging) R56AG074001U.S. Department of Health & Human Services | NIH | National Institute on Aging (U.S. National Institute on Aging) RF1AG082211U.S. Department of Health & Human Services | NIH | National Institute on Aging (U.S. National Institute on Aging) U01AG073323
Abstract
To assist the translation of genetic findings to disease pathobiology and therapeutics discovery, we present an ensemble deep learning framework, termed PIONEER (Protein-protein InteractiOn iNtErfacE pRediction), that predicts protein-binding partner-specific interfaces for all known protein interactions in humans and seven other common model organisms to generate comprehensive structurally informed protein interactomes. We demonstrate that PIONEER outperforms existing state-of-the-art methods and experimentally validate its predictions. We show that disease-associated mutations are enriched in PIONEER-predicted protein-protein interfaces and explore their impact on disease prognosis and drug responses. We identify 586 significant protein-protein interactions (PPIs) enriched with PIONEER-predicted interface somatic mutations (termed oncoPPIs) from analysis of approximately 11,000 whole exomes across 33 cancer types and show significant associations of oncoPPIs with patient survival and drug responses. PIONEER, implemented as both a web server platform and a software package, identifies functional consequences of disease-associated alleles and offers a deep learning tool for precision medicine at multiscale interactome network levels.
Indexed as
MutationNeoplasmsProtein Interaction MappingProtein Interaction MapsProteomeDeep LearningHumansProtein BindingSoftwareProteome
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