Tighter Ligand Binding Can Compensate for Impaired Stability of an RNA-Binding Protein
It has been widely shown that ligand-binding residues, by virtue of their orientation, charge, and solvent exposure, often have a net destabilizing effect on proteins that is offset by stability conferring residues elsewhere in the protein. This structure-function trade-off can constrain possible ad...
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| Format: | Journal Article |
| Language: | English |
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AMER CHEMICAL SOC
2018
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| Subjects: | |
| Online Access: | http://purl.org/au-research/grants/arc/DP140104111 http://hdl.handle.net/20.500.11937/91509 |
| _version_ | 1848765533726441472 |
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| author | Wallis, C.P. Richman, T.R. Filipovska, A. Rackham, Oliver |
| author_facet | Wallis, C.P. Richman, T.R. Filipovska, A. Rackham, Oliver |
| author_sort | Wallis, C.P. |
| building | Curtin Institutional Repository |
| collection | Online Access |
| description | It has been widely shown that ligand-binding residues, by virtue of their orientation, charge, and solvent exposure, often have a net destabilizing effect on proteins that is offset by stability conferring residues elsewhere in the protein. This structure-function trade-off can constrain possible adaptive evolutionary changes of function and may hamper protein engineering efforts to design proteins with new functions. Here, we present evidence from a large randomized mutant library screen that, in the case of PUF RNA-binding proteins, this structural relationship may be inverted and that active-site mutations that increase protein activity are also able to compensate for impaired stability. We show that certain mutations in RNA-protein binding residues are not necessarily destabilizing and that increased ligand-binding can rescue an insoluble, unstable PUF protein. We hypothesize that these mutations restabilize the protein via thermodynamic coupling of protein folding and RNA binding. © |
| first_indexed | 2025-11-14T11:36:46Z |
| format | Journal Article |
| id | curtin-20.500.11937-91509 |
| institution | Curtin University Malaysia |
| institution_category | Local University |
| language | English |
| last_indexed | 2025-11-14T11:36:46Z |
| publishDate | 2018 |
| publisher | AMER CHEMICAL SOC |
| recordtype | eprints |
| repository_type | Digital Repository |
| spelling | curtin-20.500.11937-915092023-05-04T06:35:42Z Tighter Ligand Binding Can Compensate for Impaired Stability of an RNA-Binding Protein Wallis, C.P. Richman, T.R. Filipovska, A. Rackham, Oliver Science & Technology Life Sciences & Biomedicine Biochemistry & Molecular Biology 23S RIBOSOMAL-RNA DELETERIOUS MUTATIONS ANTIBIOTIC-RESISTANCE MODULAR RECOGNITION FUNCTION TRADEOFFS STRUCTURAL BASES FOLDING ACTIVITY NUCLEIC-ACIDS DOMAIN-V EVOLUTION Catalytic Domain Humans Ligands Mutagenesis, Site-Directed Mutation Protein Binding Protein Folding Protein Stability RNA RNA-Binding Proteins Humans RNA-Binding Proteins RNA Ligands Mutagenesis, Site-Directed Catalytic Domain Protein Binding Protein Folding Mutation Protein Stability It has been widely shown that ligand-binding residues, by virtue of their orientation, charge, and solvent exposure, often have a net destabilizing effect on proteins that is offset by stability conferring residues elsewhere in the protein. This structure-function trade-off can constrain possible adaptive evolutionary changes of function and may hamper protein engineering efforts to design proteins with new functions. Here, we present evidence from a large randomized mutant library screen that, in the case of PUF RNA-binding proteins, this structural relationship may be inverted and that active-site mutations that increase protein activity are also able to compensate for impaired stability. We show that certain mutations in RNA-protein binding residues are not necessarily destabilizing and that increased ligand-binding can rescue an insoluble, unstable PUF protein. We hypothesize that these mutations restabilize the protein via thermodynamic coupling of protein folding and RNA binding. © 2018 Journal Article http://hdl.handle.net/20.500.11937/91509 10.1021/acschembio.8b00424 English http://purl.org/au-research/grants/arc/DP140104111 http://purl.org/au-research/grants/arc/DP170103000 http://purl.org/au-research/grants/arc/DP180101656 AMER CHEMICAL SOC fulltext |
| spellingShingle | Science & Technology Life Sciences & Biomedicine Biochemistry & Molecular Biology 23S RIBOSOMAL-RNA DELETERIOUS MUTATIONS ANTIBIOTIC-RESISTANCE MODULAR RECOGNITION FUNCTION TRADEOFFS STRUCTURAL BASES FOLDING ACTIVITY NUCLEIC-ACIDS DOMAIN-V EVOLUTION Catalytic Domain Humans Ligands Mutagenesis, Site-Directed Mutation Protein Binding Protein Folding Protein Stability RNA RNA-Binding Proteins Humans RNA-Binding Proteins RNA Ligands Mutagenesis, Site-Directed Catalytic Domain Protein Binding Protein Folding Mutation Protein Stability Wallis, C.P. Richman, T.R. Filipovska, A. Rackham, Oliver Tighter Ligand Binding Can Compensate for Impaired Stability of an RNA-Binding Protein |
| title | Tighter Ligand Binding Can Compensate for Impaired Stability of an RNA-Binding Protein |
| title_full | Tighter Ligand Binding Can Compensate for Impaired Stability of an RNA-Binding Protein |
| title_fullStr | Tighter Ligand Binding Can Compensate for Impaired Stability of an RNA-Binding Protein |
| title_full_unstemmed | Tighter Ligand Binding Can Compensate for Impaired Stability of an RNA-Binding Protein |
| title_short | Tighter Ligand Binding Can Compensate for Impaired Stability of an RNA-Binding Protein |
| title_sort | tighter ligand binding can compensate for impaired stability of an rna-binding protein |
| topic | Science & Technology Life Sciences & Biomedicine Biochemistry & Molecular Biology 23S RIBOSOMAL-RNA DELETERIOUS MUTATIONS ANTIBIOTIC-RESISTANCE MODULAR RECOGNITION FUNCTION TRADEOFFS STRUCTURAL BASES FOLDING ACTIVITY NUCLEIC-ACIDS DOMAIN-V EVOLUTION Catalytic Domain Humans Ligands Mutagenesis, Site-Directed Mutation Protein Binding Protein Folding Protein Stability RNA RNA-Binding Proteins Humans RNA-Binding Proteins RNA Ligands Mutagenesis, Site-Directed Catalytic Domain Protein Binding Protein Folding Mutation Protein Stability |
| url | http://purl.org/au-research/grants/arc/DP140104111 http://purl.org/au-research/grants/arc/DP140104111 http://purl.org/au-research/grants/arc/DP140104111 http://hdl.handle.net/20.500.11937/91509 |