ArticleHuman mutation2017
Whole-protein alanine-scanning mutagenesis of allostery: A large percentage of a protein can contribute to mechanism.
Article in Human mutation, 2017. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 36 papers.
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Who cites it
36 citing papers in PubMed, 61 citations in OpenAlex.
- Prion propagation is controlled by discrete structural regions of PrP rather than overall stability.The Journal of biological chemistry · 2026Article
- The genetic architecture of an allosteric hormone receptor.Nature communications · 2026Article
- Engineering a Stable Grb2 Monomer: The W60A Mutation Disrupts Dimerization but Preserves Structural Integrity.ACS omega · 2026Article
- Selective control of ligand binding through a distal mutation that alters the protein native ensemble.Proceedings of the National Academy of Sciences of the United States of America · 2026Article
- Dissecting the effects of single amino acid substitutions in SARS-CoV-2 Mpro.Protein science : a publication of the Protein Society · 2025Article
- Rheostatic contributions to protein stability can obscure a position's functional role.Protein science : a publication of the Protein Society · 2024Article
- Rheostats, toggles, and neutrals, Oh my! A new framework for understanding how amino acid changes modulate protein function.The Journal of biological chemistry · 2024Review
- CAGI, the Critical Assessment of Genome Interpretation, establishes progress and prospects for computational genetic variant interpretation methods.Genome biology · 2024Article
- The intrinsically disordered transcriptional activation domain of CIITA is functionally tuneable by single substitutions: An exception or a new paradigm?Protein science : a publication of the Protein Society · 2024Article
- The 2.4 Å structure of Zymomonas mobilis pyruvate kinase: Implications for stability and regulation.Archives of biochemistry and biophysics · 2023Article
- Divalent cations in human liver pyruvate kinase exemplify the combined effects of complex-equilibrium and allosteric regulation.Scientific reports · 2023Article
- PYK-SubstitutionOME: an integrated database containing allosteric coupling, ligand affinity and mutational, structural, pathological, bioinformatic and computational information about pyruvate kinase isozymes.Database : the journal of biological databases and curation · 2023Article
- Serendipitous Identification of a Covalent Activator of Liver Pyruvate Kinase.Chembiochem : a European journal of chemical biology · 2023Article
- Ensemble origins and distance-dependence of long-range mutational effects in proteins.iScience · 2022Article
- Odd one out? Functional tuning of Zymomonas mobilis pyruvate kinase is narrower than its allosteric, human counterpart.Protein science : a publication of the Protein Society · 2022Article
- High throughput and quantitative enzymology in the genomic era.Current opinion in structural biology · 2021Review
- uPIC-M: Efficient and Scalable Preparation of Clonal Single Mutant Libraries for High-Throughput Protein Biochemistry.ACS omega · 2021Article
- Rheostat functional outcomes occur when substitutions are introduced at nonconserved positions that diverge with speciation.Protein science : a publication of the Protein Society · 2021Article
- Article
- A hierarchy of coupling free energies underlie the thermodynamic and functional architecture of protein structures.Current research in structural biology · 2021Review
Corrections and comments
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Authors and funding
2 authors at 1 institution in 1 country.
Funding
Abstract
Many studies of allosteric mechanisms use limited numbers of mutations to test whether residues play "key" roles. However, if a large percentage of the protein contributes to allosteric function, mutating any residue would have a high probability of modifying allostery. Thus, a predicted mechanism that is dependent on only a few residues could erroneously appear to be supported. We used whole-protein alanine-scanning mutagenesis to determine which amino acid sidechains of human liver pyruvate kinase (hL-PYK; approved symbol PKLR) contribute to regulation by fructose-1,6-bisphosphate (Fru-1,6-BP; activator) and alanine (inhibitor). Each nonalanine/nonglycine residue of hL-PYK was mutated to alanine to generate 431 mutant proteins. Allosteric functions in active proteins were quantified by following substrate affinity over a concentration range of effectors. Results show that different residues contribute to the two allosteric functions. Only a small fraction of mutated residues perturbed inhibition by alanine. In contrast, a large percentage of mutated residues influenced activation by Fru-1,6-BP; inhibition by alanine is not simply the reverse of activation by Fru-1,6-BP. Moreover, the results show that Fru-1,6-BP activation would be extremely difficult to elucidate using a limited number of mutations. Additionally, this large mutational data set will be useful to train and test computational algorithms aiming to predict allosteric mechanisms.
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