ArticleProceedings of the National Academy of Sciences of the United States of America2022
Mutant libraries reveal negative design shielding proteins from supramolecular self-assembly and relocalization in cells.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 21 papers.
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Who cites it
21 citing papers in PubMed, 34 citations in OpenAlex.
- A pharmacological modality to sequester homomeric proteins.Nature chemical biology · 2026Article
- Negative design enables cell-free expression and folding of designed transmembrane β-barrels.Proceedings of the National Academy of Sciences of the United States of America · 2026Article
- Beyond contacts: The important role of the support region in protein complex assembly.Protein science : a publication of the Protein Society · 2026Article
- Construction of artificial organellesChemical science · 2025Review
- Mutation-induced filaments of folded proteins are inert and non-toxic in a cellular system.Molecular systems biology · 2025Article
- Filamentation-driven peripheral clustering of the inducible lysine decarboxylase is crucial for E. coli acid stress response.Communications biology · 2025Article
- Evolutionarily divergent Mycobacterium tuberculosis CTP synthase filaments are under selective pressure.Nature communications · 2025Article
- Symmetry facilitated the evolution of heterospecificity and high-order stoichiometry in vertebrate hemoglobin.Proceedings of the National Academy of Sciences of the United States of America · 2025Article
- Symmetry facilitated the evolution of heterospecificity and high-order stoichiometry in vertebrate hemoglobin.bioRxiv : the preprint server for biology · 2024Article
- Structural basis for allosteric regulation of human phosphofructokinase-1.Nature communications · 2024Article
- Architecture and regulation of filamentous human cystathionine beta-synthase.Nature communications · 2024Article
- Structural basis for allosteric regulation of human phosphofructokinase-1.bioRxiv : the preprint server for biology · 2024Article
- Agglomeration: when folded proteins clump together.Biophysical reviews · 2023Review
- Marginal specificity in protein interactions constrains evolution of a paralogous family.Proceedings of the National Academy of Sciences of the United States of America · 2023Article
- An Assessment of Quaternary Structure Functionality in Homomer Protein Complexes.Molecular biology and evolution · 2023Article
- Greater than the sum of parts: Mechanisms of metabolic regulation by enzyme filaments.Current opinion in structural biology · 2023Review
- Unraveling the functional consequences of a novel germline missense mutation (R38C) in the yeast model of succinate dehydrogenase subunit B: insights into neurodegenerative disorders.Frontiers in molecular neuroscience · 2023Article
- How gene duplication diversifies the landscape of protein oligomeric state and function.Current opinion in genetics & development · 2022Review
- Active site center redesign increases protein stability preserving catalysis in thioredoxin.Protein science : a publication of the Protein Society · 2022Article
- Structural plasticity enables evolution and innovation of RuBisCO assemblies.Science advances · 2022Article
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Authors and funding
5 authors at 1 institution in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Understanding the molecular consequences of mutations in proteins is essential to map genotypes to phenotypes and interpret the increasing wealth of genomic data. While mutations are known to disrupt protein structure and function, their potential to create new structures and localization phenotypes has not yet been mapped to a sequence space. To map this relationship, we employed two homo-oligomeric protein complexes in which the internal symmetry exacerbates the impact of mutations. We mutagenized three surface residues of each complex and monitored the mutations' effect on localization and assembly phenotypes in yeast cells. While surface mutations are classically viewed as benign, our analysis of several hundred mutants revealed they often trigger three main phenotypes in these proteins: nuclear localization, the formation of puncta, and fibers. Strikingly, more than 50% of random mutants induced one of these phenotypes in both complexes. Analyzing the mutant's sequences showed that surface stickiness and net charge are two key physicochemical properties associated with these changes. In one complex, more than 60% of mutants self-assembled into fibers. Such a high frequency is explained by negative design: charged residues shield the complex from self-interacting with copies of itself, and the sole removal of the charges induces its supramolecular self-assembly. A subsequent analysis of several other complexes targeted with alanine mutations suggested that such negative design is common. These results highlight that minimal perturbations in protein surfaces' physicochemical properties can frequently drive assembly and localization changes in a cellular context.
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