ArticleeLife2016
Determination of ubiquitin fitness landscapes under different chemical stresses in a classroom setting.
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Article in eLife, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 53 papers.
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53citing papers in PubMed
7.0field-weighted citation impact, top 3% of its field
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Who cites it
53 citing papers in PubMed, 95 citations in OpenAlex.
- Scanning the horizon: deep mutational scanning approaches in virology.Journal of virology · 2026Review
- Overestimating zero-shot fitness prediction: Broad benchmarks mask local failures and practical limitations.bioRxiv : the preprint server for biology · 2026Article
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- SynFit: Synergistic Contrastive Learning for Multi-Objective Protein Fitness Prediction and Optimization.bioRxiv : the preprint server for biology · 2026Article
- Massively parallel functional genomic assays in endocrinology: from promise to delivery.Journal of molecular endocrinology · 2026Review
- Engineering of genetically encoded programmable calcium channel inhibitory binders.Nature communications · 2026Article
- Amino acid substitutions at rheostat positions in the NaProtein science : a publication of the Protein Society · 2025Article
- Dissecting the effects of single amino acid substitutions in SARS-CoV-2 Mpro.Protein science : a publication of the Protein Society · 2025Article
- MMRT: MultiMut Recursive Tree for predicting functional effects of high-order protein variants from low-order variants.Computational and structural biotechnology journal · 2025Article
- The ubiquitin-proteasome system in circadian regulation.Frontiers in neuroscience · 2025Review
- Expert-guided protein language models enable accurate and blazingly fast fitness prediction.Bioinformatics (Oxford, England) · 2024Article
- Article
- Deep mutational scanning of EccDbioRxiv : the preprint server for biology · 2024Article
- A systematic analysis of regression models for protein engineering.PLoS computational biology · 2024Article
- ProteinGym: Large-Scale Benchmarks for Protein Design and Fitness Prediction.bioRxiv : the preprint server for biology · 2023Article
- Ensemble Learning with Supervised Methods Based on Large-Scale Protein Language Models for Protein Mutation Effects Prediction.International journal of molecular sciences · 2023Article
- Systematic conformation-to-phenotype mapping via limited deep sequencing of proteins.Molecular cell · 2023Article
- Deep Mutational Scanning of an Oxygen-Independent Fluorescent Protein CreiLOV for Comprehensive Profiling of Mutational and Epistatic Effects.ACS synthetic biology · 2023Article
- Fitness and Functional Landscapes of the E. coli RNase III Gene rnc.Molecular biology and evolution · 2023Article
- Mutational fitness landscape and drug resistance.Current opinion in structural biology · 2023Review
Corrections and comments
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Authors and funding
41 authors at 4 institutions in 1 country.
David MavorBiophysics Graduate Group, University of California, San Francisco, San Francisco, United States.
Kyle BarlowBioinformatics Graduate Group, University of California, San Francisco, San Francisco, United States.ORCID 0000-0002-9787-0066
Samuel ThompsonBiophysics Graduate Group, University of California, San Francisco, San Francisco, United States.
Benjamin A BaradBiophysics Graduate Group, University of California, San Francisco, San Francisco, United States.
Alain R BonnyBiophysics Graduate Group, University of California, San Francisco, San Francisco, United States.
Clinton L CarioBioinformatics Graduate Group, University of California, San Francisco, San Francisco, United States.
Garrett GaskinsBioinformatics Graduate Group, University of California, San Francisco, San Francisco, United States.
Zairan LiuBiophysics Graduate Group, University of California, San Francisco, San Francisco, United States.
Laura DemingHoward Hughes Medical Institute, University of California, San Francisco, San Francisco, United States.
Seth D AxenBioinformatics Graduate Group, University of California, San Francisco, San Francisco, United States.
Elena CaceresBioinformatics Graduate Group, University of California, San Francisco, San Francisco, United States.
Weilin ChenBioinformatics Graduate Group, University of California, San Francisco, San Francisco, United States.
Adolfo CuestaChemistry and Chemical Biology Graduate Program, University of California, San Francisco, San Francisco, United States.
Rachel E GateBioinformatics Graduate Group, University of California, San Francisco, San Francisco, United States.
Evan M GreenBiophysics Graduate Group, University of California, San Francisco, San Francisco, United States.
Kaitlin R HulceChemistry and Chemical Biology Graduate Program, University of California, San Francisco, San Francisco, United States.
Weiyue JiBiophysics Graduate Group, University of California, San Francisco, San Francisco, United States.
Lillian R KennerBiophysics Graduate Group, University of California, San Francisco, San Francisco, United States.
Bruk MensaChemistry and Chemical Biology Graduate Program, University of California, San Francisco, San Francisco, United States.
Leanna S MorinishiBioinformatics Graduate Group, University of California, San Francisco, San Francisco, United States.
Steven M MossChemistry and Chemical Biology Graduate Program, University of California, San Francisco, San Francisco, United States.
Marco MravicBiophysics Graduate Group, University of California, San Francisco, San Francisco, United States.
Ryan K MuirChemistry and Chemical Biology Graduate Program, University of California, San Francisco, San Francisco, United States.
Stefan NiekampBiophysics Graduate Group, University of California, San Francisco, San Francisco, United States.
Chimno I NnadiChemistry and Chemical Biology Graduate Program, University of California, San Francisco, San Francisco, United States.
Eugene PalovcakBiophysics Graduate Group, University of California, San Francisco, San Francisco, United States.
Erin M PossChemistry and Chemical Biology Graduate Program, University of California, San Francisco, San Francisco, United States.
Tyler D RossBiophysics Graduate Group, University of California, San Francisco, San Francisco, United States.
Eugenia C SalcedoChemistry and Chemical Biology Graduate Program, University of California, San Francisco, San Francisco, United States.
Stephanie K SeeChemistry and Chemical Biology Graduate Program, University of California, San Francisco, San Francisco, United States.
Meena SubramaniamBioinformatics Graduate Group, University of California, San Francisco, San Francisco, United States.
Allison W WongChemistry and Chemical Biology Graduate Program, University of California, San Francisco, San Francisco, United States.
Jennifer LiUCSF Science and Health Education Partnership, University of California, San Francisco, San Francisco, United States.
Kurt S ThornDepartment of Biochemistry and Biophysics, University of California, San Francisco, San Francisco, United States.
Shane Ó ConchúirDepartment of Bioengineering and Therapeutic Sciences, California Institute for Quantitative Biology, University of California, San Francisco, San Francisco, United States.
Benjamin P RoscoeDepartment of Biochemistry and Molecular Pharmacology, University of Massachusetts Medical School, Worcester, United States.
Eric D ChowDepartment of Biochemistry and Biophysics, University of California, San Francisco, San Francisco, United States.
Joseph L DeRisiHoward Hughes Medical Institute, University of California, San Francisco, San Francisco, United States.
Tanja KortemmeDepartment of Bioengineering and Therapeutic Sciences, California Institute for Quantitative Biology, University of California, San Francisco, San Francisco, United States.
Daniel N BolonDepartment of Biochemistry and Molecular Pharmacology, University of Massachusetts Medical School, Worcester, United States.
James S FraserDepartment of Bioengineering and Therapeutic Sciences, California Institute for Quantitative Biology, University of California, San Francisco, San Francisco, United States.ORCID 0000-0002-5080-2859
University of California, San Francisco · USQB3 · USHoward Hughes Medical Institute · USUniversity of Massachusetts Chan Medical School · US
Funding
MEDICAL SCIENTIST TRAINING PROGRAMT32GM007618 · NIGMS · UNIVERSITY OF CALIFORNIA, SAN FRANCISCO · PI ANDERSON, MARK S · 1985 to 2020
$29.6MSTRUCTURAL BIOLOGY TRAINING PROGRAMT32GM008284 · NIGMS · UNIVERSITY OF CALIFORNIA, SAN FRANCISCO · PI KORTEMME, TANJA · 1988 to 2022
$10.1MRESEARCH TRAINING IN CHEMISTRY AND CHEMICAL BIOLOGYT32GM064337 · NIGMS · UNIVERSITY OF CALIFORNIA, SAN FRANCISCO · PI CRAIK, CHARLES SCOTT · 2002 to 2021
$7.8MBMI Bioinformatics Training GrantsT32GM067547 · NIGMS · UNIVERSITY OF CALIFORNIA, SAN FRANCISCO · PI HERNANDEZ, RYAN D. · 2003 to 2022
$6.6MIntegrative Program in Complex Biological System (ipCBS)T32EB009383 · NIBIB · UNIVERSITY OF CALIFORNIA, SAN FRANCISCO · PI MARSHALL, WALLACE, WEINER, ORION D · 2009 to 2022
$3.2MRelating protein interaction networks to physiology by systematic mutant analysesR01GM112844 · NIGMS · UNIV OF MASSACHUSETTS MED SCH WORCESTER · PI BOLON, DANIEL N · 2015 to 2023
$2.7MComputational design of protein-based small-molecule biosensorsR01GM110089 · NIGMS · UNIVERSITY OF CALIFORNIA, SAN FRANCISCO · PI KORTEMME, TANJA · 2015 to 2022
$2.3MDiscovery of Protein Network FunctionR01GM117189 · NIGMS · UNIVERSITY OF CALIFORNIA, SAN FRANCISCO · PI KORTEMME, TANJA · 2016 to 2019
$2.2MThe Impact of Mutation on the Conformations and Recognition of UbiquitinDP5OD009180 · OD · UNIVERSITY OF CALIFORNIA, SAN FRANCISCO · PI FRASER, JAMES SOLOMON · 2011 to 2015
$1.8MNIBIB NIH HHS T32 EB009383NIGMS NIH HHS R01 GM110089NIGMS NIH HHS R01 GM112844NIGMS NIH HHS R01 GM117189NIGMS NIH HHS T32 GM007618NIGMS NIH HHS T32 GM008284NIGMS NIH HHS T32 GM064337NIGMS NIH HHS T32 GM067547NIH HHS DP5 OD009180
Abstract
Ubiquitin is essential for eukaryotic life and varies in only 3 amino acid positions between yeast and humans. However, recent deep sequencing studies indicate that ubiquitin is highly tolerant to single mutations. We hypothesized that this tolerance would be reduced by chemically induced physiologic perturbations. To test this hypothesis, a class of first year UCSF graduate students employed deep mutational scanning to determine the fitness landscape of all possible single residue mutations in the presence of five different small molecule perturbations. These perturbations uncover 'shared sensitized positions' localized to areas around the hydrophobic patch and the C-terminus. In addition, we identified perturbation specific effects such as a sensitization of His68 in HU and a tolerance to mutation at Lys63 in DTT. Our data show how chemical stresses can reduce buffering effects in the ubiquitin proteasome system. Finally, this study demonstrates the potential of lab-based interdisciplinary graduate curriculum.
Indexed as
DNA Mutational AnalysisStress, PhysiologicalBiologyHumansMutant ProteinsProteasome Endopeptidase ComplexSaccharomyces cerevisiaeStudentsUbiquitinUniversitiesMutant ProteinsProteasome Endopeptidase ComplexUbiquitinbiophysicschemical biologycomputational biologydeep mutational scanningevolutionary biologygenomicsproteasomeproteostasisS. cerevisiaesystems biologyubiquitin
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