ArticleScientific reports2019
Functional tunability from a distance: Rheostat positions influence allosteric coupling between two distant binding sites.
Article in Scientific reports, 2019. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 19 papers.
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Who cites it
19 citing papers in PubMed, 24 citations in OpenAlex.
- 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
- Identification of positions in human aldolase a that are neutral for apparent KArchives of biochemistry and biophysics · 2024Article
- Dynamics-based protein network features accurately discriminate neutral and rheostat positions.Biophysical journal · 2024Article
- 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
- 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
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- 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
- 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
- Structural Plasticity Is a Feature of Rheostat Positions in the Human NaInternational journal of molecular sciences · 2022Article
- Substitutions at a rheostat position in human aldolase A cause a shift in the conformational population.Protein science : a publication of the Protein Society · 2022Article
- Rheostat functional outcomes occur when substitutions are introduced at nonconserved positions that diverge with speciation.Protein science : a publication of the Protein Society · 2021Article
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- Rheostat positions: A new classification of protein positions relevant to pharmacogenomics.Medicinal chemistry research : an international journal for rapid communications on design and mechanisms of action of biologically active agents · 2020Article
- Substitutions at rheostat position 52 of LacI have long-range effects on the LacI conformational landscape.Biophysical chemistryArticle
- A clinically relevant polymorphism in the NaThe Journal of biological chemistryArticle
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Authors and funding
3 authors at 1 institution in 1 country.
Funding
Abstract
For protein mutagenesis, a common expectation is that important positions will behave like on/off "toggle" switches (i.e., a few substitutions act like wildtype, most abolish function). However, there exists another class of important positions that manifests a wide range of functional outcomes upon substitution: "rheostat" positions. Previously, we evaluated rheostat positions located near the allosteric binding sites for inhibitor alanine (Ala) and activator fructose-1,6-bisphosphate (Fru-1,6-BP) in human liver pyruvate kinase. When substituted with multiple amino acids, many positions demonstrated moderate rheostatic effects on allosteric coupling between effector binding and phosphoenolpyruvate (PEP) binding in the active site. Nonetheless, the combined outcomes of all positions sampled the full range of possible allosteric coupling (full tunability). However, that study only evaluated allosteric tunability of "local" positions, i.e., positions were located near the binding sites of the allosteric ligand being assessed. Here, we evaluated tunability of allosteric coupling when mutated sites were distant from the allosterically-coupled binding sites. Positions near the Ala binding site had rheostatic outcomes on allosteric coupling between Fru-1,6-BP and PEP binding. In contrast, positions in the Fru-1,6-BP site exhibited modest effects on coupling between Ala and PEP binding. Analyzed in aggregate, both PEP/Ala and PEP/Fru-1,6-BP coupling were again fully tunable by amino acid substitutions at this limited set of distant positions. Furthermore, some positions exhibited rheostatic control over multiple parameters and others exhibited rheostatic effects on one parameter and toggle control over a second. These findings highlight challenges in efforts to both predict/interpret mutational outcomes and engineer functions into proteins.
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