ArticleScience (New York, N.Y.)2020
Genetic interaction mapping informs integrative structure determination of protein complexes.
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Article in Science (New York, N.Y.), 2020. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 17 papers.
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17 citing papers in PubMed.
- GiGCN: a network-based framework for uncovering synthetic lethal and viable genetic interactions.Briefings in bioinformatics · 2026Article
- Protein-protein interactions are a major source of epistasis in genetic interaction networks.Nature communications · 2026Article
- Epigenetic regulation of intracellular branched-chain amino acid homeostasis maintains a normal lifespan.iScience · 2025Article
- Frontiers in integrative structural modeling of macromolecular assemblies.QRB discovery · 2025Review
- The functional mutational landscape of theiScience · 2023Article
- Context-defined cancer co-dependency mapping identifies a functional interplay between PRC2 and MLL-MEN1 complex in lymphoma.Nature communications · 2023Article
- Integrative structure determination of histones H3 and H4 using genetic interactions.The FEBS journal · 2023Article
- Identification, expression, and purification of DNA cytosine 5-methyltransferases with short recognition sequences.BMC biotechnology · 2022Article
- A multiplexed, three-dimensional pooling and next-generation sequencing strategy for creating barcoded mutant arrays: construction of a Schizosaccharomyces pombe transposon insertion library.Nucleic acids research · 2022Article
- Article
- From systems to structure - using genetic data to model protein structures.Nature reviews. Genetics · 2022Review
- Protocol for RNA-seq Expression Analysis in Yeast.Bio-protocol · 2021Article
- Mapping the multiscale structure of biological systems.Cell systems · 2021Review
- Chemical-genetic interrogation of RNA polymerase mutants reveals structure-function relationships and physiological tradeoffs.Molecular cell · 2021Article
- Setting molecular traps in yeast for identification of anticancer drug targets.Proceedings of the National Academy of Sciences of the United States of America · 2021Article
- Characterization of an A3G-VifMolecular & cellular proteomics : MCP · 2021Article
- From integrative structural biology to cell biology.The Journal of biological chemistryReview
Corrections and comments
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Authors and funding
28 authors.
Hannes Braberg *Department of Cellular and Molecular Pharmacology, University of California, San Francisco, San Francisco, CA 94158, USA.ORCID 0000-0002-7070-2257
Ignacia Echeverria *Department of Cellular and Molecular Pharmacology, University of California, San Francisco, San Francisco, CA 94158, USA.ORCID 0000-0003-4717-1467
Stefan Bohn *Department of Cellular and Molecular Pharmacology, University of California, San Francisco, San Francisco, CA 94158, USA.ORCID 0000-0001-9196-622X
Peter Cimermancic *Department of Bioengineering and Therapeutic Sciences, University of California, San Francisco, San Francisco, CA 94158, USA.ORCID 0000-0002-2802-7649
Anthony ShiverGraduate Group in Biophysics, University of California San Francisco, San Francisco, CA 94158, USA.ORCID 0000-0001-7094-3715
Richard AlexanderDepartment of Cellular and Molecular Pharmacology, University of California, San Francisco, San Francisco, CA 94158, USA.ORCID 0000-0002-0839-3537
Jiewei XuDepartment of Cellular and Molecular Pharmacology, University of California, San Francisco, San Francisco, CA 94158, USA.ORCID 0000-0002-8647-4172
Michael ShalesDepartment of Cellular and Molecular Pharmacology, University of California, San Francisco, San Francisco, CA 94158, USA.
Raghuvar DronamrajuDepartment of Biochemistry and Biophysics, University of North Carolina School of Medicine, Chapel Hill, NC 27599, USA.
Shuangying JiangCAS Key Laboratory of Quantitative Engineering Biology, Guangdong Provincial Key Laboratory of Synthetic Genomics and Shenzhen Key Laboratory of Synthetic Genomics, Shenzhen Institute of Synthetic Biology, Shenzhen Institutes of Advanced Technology, Chinese Academy of Sciences, Shenzhen 518055, China.
Gajendradhar DwivediDepartment of Biology and Rosenstiel Basic Medical Sciences Research Center, Brandeis University, Waltham, MA 02454, USA.
Derek BogdanoffCenter for Advanced Technology, Department of Biophysics and Biochemistry, University of California, San Francisco, San Francisco, CA 94158, USA.
Kaitlin K ChaungCenter for Advanced Technology, Department of Biophysics and Biochemistry, University of California, San Francisco, San Francisco, CA 94158, USA.ORCID 0000-0002-0397-1430
Ruth HüttenhainDepartment of Cellular and Molecular Pharmacology, University of California, San Francisco, San Francisco, CA 94158, USA.ORCID 0000-0002-0896-5910
Shuyi WangDepartment of Cellular and Molecular Pharmacology, University of California, San Francisco, San Francisco, CA 94158, USA.
David MavorQuantitative Biosciences Institute, University of California, San Francisco, San Francisco, CA 94158, USA.
Riccardo PellarinDepartment of Bioengineering and Therapeutic Sciences, University of California, San Francisco, San Francisco, CA 94158, USA.ORCID 0000-0002-1054-7400
Dina SchneidmanDepartment of Bioengineering and Therapeutic Sciences, University of California, San Francisco, San Francisco, CA 94158, USA.ORCID 0000-0003-0480-0438
Joel S BaderDepartment of Biomedical Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.ORCID 0000-0002-6020-4625
James S FraserQuantitative Biosciences Institute, University of California, San Francisco, San Francisco, CA 94158, USA.ORCID 0000-0002-5080-2859
John MorrisDepartment of Pharmaceutical Chemistry, University of California, San Francisco, San Francisco, CA 94158, USA.ORCID 0000-0003-0290-7979
James E HaberDepartment of Biology and Rosenstiel Basic Medical Sciences Research Center, Brandeis University, Waltham, MA 02454, USA.
Brian D StrahlDepartment of Biochemistry and Biophysics, University of North Carolina School of Medicine, Chapel Hill, NC 27599, USA.
Carol A GrossDepartment of Microbiology and Immunology and Department of Cell and Tissue Biology, University of California, San Francisco, San Francisco, CA 94158, USA.
Junbiao DaiCAS Key Laboratory of Quantitative Engineering Biology, Guangdong Provincial Key Laboratory of Synthetic Genomics and Shenzhen Key Laboratory of Synthetic Genomics, Shenzhen Institute of Synthetic Biology, Shenzhen Institutes of Advanced Technology, Chinese Academy of Sciences, Shenzhen 518055, China.ORCID 0000-0002-5299-4700
Jef D BoekeNYU Langone Health, New York, NY 10016, USA. nevan.krogan@ucsf.edu sali@salilab.org jef.boeke@nyulangone.org.ORCID 0000-0001-5322-4946
Andrej SaliQuantitative Biosciences Institute, University of California, San Francisco, San Francisco, CA 94158, USA. nevan.krogan@ucsf.edu sali@salilab.org jef.boeke@nyulangone.org.ORCID 0000-0003-0435-6197
Nevan J KroganDepartment of Cellular and Molecular Pharmacology, University of California, San Francisco, San Francisco, CA 94158, USA. nevan.krogan@ucsf.edu sali@salilab.org jef.boeke@nyulangone.org.ORCID 0000-0003-4902-337X
Funding
X-ray Screening and Rapid Structure DeterminationP50GM082250 · NIGMS · UNIVERSITY OF CALIFORNIA, SAN FRANCISCO · PI FRANKEL, ALAN D · 2007 to 2018
$48.8MTCP5: ACTIVE SITE LABELING REAGENT FOR ACETYLTRANSFERASESU54RR020839 · NCRR · JOHNS HOPKINS UNIVERSITY · PI BOEKE, JEF D · 2004 to 2011
$27.4MRESEARCH PROJECT 2U19AI135990 · NIAID · UNIVERSITY OF CALIFORNIA, SAN FRANCISCO · PI Nevan J Krogan · 2018 to 2026
$21.4MTranscriptional Networks During Cardiac DifferentiationP01HL089707 · NHLBI · J. DAVID GLADSTONE INSTITUTES · PI SRIVASTAVA, DEEPAK · 2008 to 2017
$20.4MRewiring Therapeutic Cells: User-Controlled T Cells and Stem CellsP50GM081879 · NIGMS · UNIVERSITY OF CALIFORNIA, SAN FRANCISCO · PI LIM, WENDELL A · 2010 to 2017
$19.0MTR&D Project 4. The Imaging Stage: Multiscale Spatiotemporal Modeling of Macromolecular Systems in Cellular NeighborhoodsP41GM109824 · NIGMS · ROCKEFELLER UNIVERSITY · PI ROUT, MICHAEL P · 2014 to 2023
$18.8MX-ray Screening and Rapid Structure DeterminationP50AI150476 · NIAID · UNIVERSITY OF CALIFORNIA, SAN FRANCISCO · PI EMERMAN, MICHAEL · 2019 to 2021
$14.4MUsing Networks to Seed Hierarchical Whole-cell Models of CancerU54CA209891 · NCI · UNIVERSITY OF CALIFORNIA, SAN FRANCISCO · PI IDEKER, TREY · 2017 to 2021
$10.9MProject 3: Autophagy dysfunction and neuronal activity in FTDU54NS100717 · NINDS · WEILL MEDICAL COLL OF CORNELL UNIV · PI CUERVO, ANA MARIA · 2016 to 2020
$10.8MSTRUCTURAL BIOLOGY TRAINING PROGRAMT32GM008284 · NIGMS · UNIVERSITY OF CALIFORNIA, SAN FRANCISCO · PI KORTEMME, TANJA · 1988 to 2022
$10.1MCellular homeostasis pathways in bacteriaR35GM118061 · NIGMS · UNIVERSITY OF CALIFORNIA, SAN FRANCISCO · PI GROSS, CAROL ANNE · 2016 to 2025
$9.0MDNA Damage Response and Repair of a Broken ChromosomeR35GM127029 · NIGMS · BRANDEIS UNIVERSITY · PI JAMES E HABER · 2018 to 2026
$8.6MNCI NIH HHS U54 CA209891NCRR NIH HHS U54 RR020839NHLBI NIH HHS P01 HL089707NIAID NIH HHS P50 AI150476NIAID NIH HHS U19 AI135990NIGMS NIH HHS P01 GM105473NIGMS NIH HHS P41 GM109824NIGMS NIH HHS P50 GM081879NIGMS NIH HHS P50 GM082250NIGMS NIH HHS R01 GM083960NIGMS NIH HHS R01 GM084279NIGMS NIH HHS R01 GM084448NIGMS NIH HHS R01 GM098101NIGMS NIH HHS R01 GM123159NIGMS NIH HHS R35 GM118061NIGMS NIH HHS R35 GM126900NIGMS NIH HHS R35 GM127029NIGMS NIH HHS T32 GM008284NIGMS NIH HHS U54 GM103520NIH HHS DP5 OD009180NIH HHS S10 OD021596NINDS NIH HHS U54 NS100717
Abstract
Determining structures of protein complexes is crucial for understanding cellular functions. Here, we describe an integrative structure determination approach that relies on in vivo measurements of genetic interactions. We construct phenotypic profiles for point mutations crossed against gene deletions or exposed to environmental perturbations, followed by converting similarities between two profiles into an upper bound on the distance between the mutated residues. We determine the structure of the yeast histone H3-H4 complex based on ~500,000 genetic interactions of 350 mutants. We then apply the method to subunits Rpb1-Rpb2 of yeast RNA polymerase II and subunits RpoB-RpoC of bacterial RNA polymerase. The accuracy is comparable to that based on chemical cross-links; using restraints from both genetic interactions and cross-links further improves model accuracy and precision. The approach provides an efficient means to augment integrative structure determination with in vivo observations.
Indexed as
HistonesMultiprotein ComplexesMutationProtein ConformationProtein Interaction MappingProtein Interaction MapsSaccharomyces cerevisiaeSaccharomyces cerevisiae ProteinsHistonesMultiprotein ComplexesSaccharomyces cerevisiae Proteins
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