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D Thirumalai - One of the best experts on this subject based on the ideXlab platform.
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molecular chaperones maximize the native state Yield on biological times by driving substrates out of equilibrium
Proceedings of the National Academy of Sciences of the United States of America, 2017Co-Authors: Shaon Chakrabarti, Changbong Hyeon, George H Lorimer, D ThirumalaiAbstract:Molecular chaperones facilitate the folding of proteins and RNA in vivo. Under physiological conditions, the in vitro folding of Tetrahymena ribozyme by the RNA chaperone CYT-19 behaves paradoxically; increasing the chaperone concentration reduces the Yield of native ribozymes. In contrast, the protein chaperone GroEL works as expected; the Yield of the native substrate increases with chaperone concentration. The discrepant chaperone-assisted ribozyme folding thus contradicts the expectation that it operates as an efficient annealing machine. To resolve this paradox, we propose a minimal stochastic model based on the Iterative Annealing Mechanism (IAM) that offers a unified description of chaperone-mediated folding of both proteins and RNA. Our theory provides a general relation that quantitatively predicts how the Yield of native states depends on chaperone concentration. Although the Absolute Yield of native states decreases in the Tetrahymena ribozyme, the product of the folding rate and the steady-state native Yield increases in both cases. By using energy from ATP hydrolysis, both CYT-19 and GroEL drive their substrate concentrations far out of equilibrium, thus maximizing the native Yield in a short time. This also holds when the substrate concentration exceeds that of GroEL. Our findings satisfy the expectation that proteins and RNA be folded by chaperones on biologically relevant time scales, even if the final Yield is lower than what equilibrium thermodynamics would dictate. The theory predicts that the quantity of chaperones in vivo has evolved to optimize native state production of the folded states of RNA and proteins in a given time.
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molecular chaperones maximize the native state Yield per unit time by driving substrates out of equilibrium
bioRxiv, 2017Co-Authors: Shaon Chakrabarti, Changbong Hyeon, George H Lorimer, D ThirumalaiAbstract:Molecular chaperones have evolved to facilitate folding of proteins and RNA in vivo where spontaneous self-assembly is sometimes prohibited. Folding of Tetrahymena ribozyme, assisted by the RNA chaperone CYT-19, surprisingly shows that at physiological Mg2+ ion concentrations, increasing the chaperone concentration reduces the Yield of native ribozymes. In contrast, the more extensively investigated protein chaperone GroEL works in exactly the opposite manner — the Yield of native substrate increases with the increase in chaperone concentration. Thus, the puzzling observation on the assisted ribozyme folding seems to contradict the expectation that a molecular chaperone acts as an efficient annealing machine. We suggest a resolution to this apparently paradoxical behavior by developing a minimal stochastic model that captures the essence of the Iterative Annealing Mechanism (IAM), providing a unified description of chaperone mediated-folding of proteins and RNA. Our theory provides a general relation involving the kinetic rates of the system, which quantitatively predicts how the Yield of native state depends on chaperone concentration. By carefully analyzing a host of experimental data on Tetrahymena (and its mutants) as well as the protein Rubisco and Malate Dehydrogenase, we show that although the Absolute Yield of native states decreases in the ribozyme, the rate of native state production increases in both the cases. By utilizing energy from ATP hydrolysis, both CYT-19 and GroEL drive their substrate concentrations far out of equilibrium, in an endeavor to maximize the native Yield in a short time. Our findings are consistent with the general expectation that proteins or RNA need to be folded by the cellular machinery on biologically relevant timescales, even if the final Yield is lower than what equilibrium thermodynamics would dictate. Besides establishing the IAM as the basis for functions of RNA and protein chaperones, our work shows that cellular copy numbers have been adjusted to optimize the rate of native state production of the folded states of RNA and proteins under physiological conditions.
Shaon Chakrabarti - One of the best experts on this subject based on the ideXlab platform.
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molecular chaperones maximize the native state Yield on biological times by driving substrates out of equilibrium
Proceedings of the National Academy of Sciences of the United States of America, 2017Co-Authors: Shaon Chakrabarti, Changbong Hyeon, George H Lorimer, D ThirumalaiAbstract:Molecular chaperones facilitate the folding of proteins and RNA in vivo. Under physiological conditions, the in vitro folding of Tetrahymena ribozyme by the RNA chaperone CYT-19 behaves paradoxically; increasing the chaperone concentration reduces the Yield of native ribozymes. In contrast, the protein chaperone GroEL works as expected; the Yield of the native substrate increases with chaperone concentration. The discrepant chaperone-assisted ribozyme folding thus contradicts the expectation that it operates as an efficient annealing machine. To resolve this paradox, we propose a minimal stochastic model based on the Iterative Annealing Mechanism (IAM) that offers a unified description of chaperone-mediated folding of both proteins and RNA. Our theory provides a general relation that quantitatively predicts how the Yield of native states depends on chaperone concentration. Although the Absolute Yield of native states decreases in the Tetrahymena ribozyme, the product of the folding rate and the steady-state native Yield increases in both cases. By using energy from ATP hydrolysis, both CYT-19 and GroEL drive their substrate concentrations far out of equilibrium, thus maximizing the native Yield in a short time. This also holds when the substrate concentration exceeds that of GroEL. Our findings satisfy the expectation that proteins and RNA be folded by chaperones on biologically relevant time scales, even if the final Yield is lower than what equilibrium thermodynamics would dictate. The theory predicts that the quantity of chaperones in vivo has evolved to optimize native state production of the folded states of RNA and proteins in a given time.
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molecular chaperones maximize the native state Yield per unit time by driving substrates out of equilibrium
bioRxiv, 2017Co-Authors: Shaon Chakrabarti, Changbong Hyeon, George H Lorimer, D ThirumalaiAbstract:Molecular chaperones have evolved to facilitate folding of proteins and RNA in vivo where spontaneous self-assembly is sometimes prohibited. Folding of Tetrahymena ribozyme, assisted by the RNA chaperone CYT-19, surprisingly shows that at physiological Mg2+ ion concentrations, increasing the chaperone concentration reduces the Yield of native ribozymes. In contrast, the more extensively investigated protein chaperone GroEL works in exactly the opposite manner — the Yield of native substrate increases with the increase in chaperone concentration. Thus, the puzzling observation on the assisted ribozyme folding seems to contradict the expectation that a molecular chaperone acts as an efficient annealing machine. We suggest a resolution to this apparently paradoxical behavior by developing a minimal stochastic model that captures the essence of the Iterative Annealing Mechanism (IAM), providing a unified description of chaperone mediated-folding of proteins and RNA. Our theory provides a general relation involving the kinetic rates of the system, which quantitatively predicts how the Yield of native state depends on chaperone concentration. By carefully analyzing a host of experimental data on Tetrahymena (and its mutants) as well as the protein Rubisco and Malate Dehydrogenase, we show that although the Absolute Yield of native states decreases in the ribozyme, the rate of native state production increases in both the cases. By utilizing energy from ATP hydrolysis, both CYT-19 and GroEL drive their substrate concentrations far out of equilibrium, in an endeavor to maximize the native Yield in a short time. Our findings are consistent with the general expectation that proteins or RNA need to be folded by the cellular machinery on biologically relevant timescales, even if the final Yield is lower than what equilibrium thermodynamics would dictate. Besides establishing the IAM as the basis for functions of RNA and protein chaperones, our work shows that cellular copy numbers have been adjusted to optimize the rate of native state production of the folded states of RNA and proteins under physiological conditions.
K. Pentlow - One of the best experts on this subject based on the ideXlab platform.
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improved Yields of iodine 124 from the enriched tellurium 124 dioxide aluminum oxide target
APPLICATION OF ACCELERATORS IN RESEARCH AND INDUSTRY: 17TH International Conference on the Application of Accelerators in Research and Industry, 2003Co-Authors: R. D. Finn, Y. Sheh, C. Lom, J. Balatoni, J. Qiao, A. Nacca, Shangde Cai, W. Bornmann, K. PentlowAbstract:The escalating clinical application of Positron Emission Tomography results from the novel radiotracers which are available to monitor specific biochemical or physiologic processes. Future developments of the technique will require an increasing availability of additional unique radioligands and radionuclides. Iodine‐124, a radionuclide whose potential for both diagnostic and therapeutic applications is widely recognized, has been prepared at Memorial Sloan‐Kettering Cancer Center on a weekly basis for several years (1). With its characteristic 4.18 day half life and complex decay scheme (2) which includes positron emission (22.0 ± 0.5%) and electron capture (78 ± 0.5%), this radionuclide has been shown to be appropriate for radiotracers describing slow physiologic processes with the clearance of non‐specific radioactivity. The refinements and modifications being engineered into the cyclotron target system to increase the Absolute Yield of recoverable radioactivity from each irradiation and its chemical p...
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improved Yields of iodine 124 from the enriched tellurium 124 dioxide aluminum oxide target
APPLICATION OF ACCELERATORS IN RESEARCH AND INDUSTRY: 17TH International Conference on the Application of Accelerators in Research and Industry, 2003Co-Authors: R. D. Finn, Y. Sheh, C. Lom, J. Balatoni, J. Qiao, A. Nacca, Shangde Cai, W. Bornmann, K. PentlowAbstract:The escalating clinical application of Positron Emission Tomography results from the novel radiotracers which are available to monitor specific biochemical or physiologic processes. Future developments of the technique will require an increasing availability of additional unique radioligands and radionuclides. Iodine‐124, a radionuclide whose potential for both diagnostic and therapeutic applications is widely recognized, has been prepared at Memorial Sloan‐Kettering Cancer Center on a weekly basis for several years (1). With its characteristic 4.18 day half life and complex decay scheme (2) which includes positron emission (22.0 ± 0.5%) and electron capture (78 ± 0.5%), this radionuclide has been shown to be appropriate for radiotracers describing slow physiologic processes with the clearance of non‐specific radioactivity. The refinements and modifications being engineered into the cyclotron target system to increase the Absolute Yield of recoverable radioactivity from each irradiation and its chemical processing of the reusable solid target matrix are described..
George H Lorimer - One of the best experts on this subject based on the ideXlab platform.
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molecular chaperones maximize the native state Yield on biological times by driving substrates out of equilibrium
Proceedings of the National Academy of Sciences of the United States of America, 2017Co-Authors: Shaon Chakrabarti, Changbong Hyeon, George H Lorimer, D ThirumalaiAbstract:Molecular chaperones facilitate the folding of proteins and RNA in vivo. Under physiological conditions, the in vitro folding of Tetrahymena ribozyme by the RNA chaperone CYT-19 behaves paradoxically; increasing the chaperone concentration reduces the Yield of native ribozymes. In contrast, the protein chaperone GroEL works as expected; the Yield of the native substrate increases with chaperone concentration. The discrepant chaperone-assisted ribozyme folding thus contradicts the expectation that it operates as an efficient annealing machine. To resolve this paradox, we propose a minimal stochastic model based on the Iterative Annealing Mechanism (IAM) that offers a unified description of chaperone-mediated folding of both proteins and RNA. Our theory provides a general relation that quantitatively predicts how the Yield of native states depends on chaperone concentration. Although the Absolute Yield of native states decreases in the Tetrahymena ribozyme, the product of the folding rate and the steady-state native Yield increases in both cases. By using energy from ATP hydrolysis, both CYT-19 and GroEL drive their substrate concentrations far out of equilibrium, thus maximizing the native Yield in a short time. This also holds when the substrate concentration exceeds that of GroEL. Our findings satisfy the expectation that proteins and RNA be folded by chaperones on biologically relevant time scales, even if the final Yield is lower than what equilibrium thermodynamics would dictate. The theory predicts that the quantity of chaperones in vivo has evolved to optimize native state production of the folded states of RNA and proteins in a given time.
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molecular chaperones maximize the native state Yield per unit time by driving substrates out of equilibrium
bioRxiv, 2017Co-Authors: Shaon Chakrabarti, Changbong Hyeon, George H Lorimer, D ThirumalaiAbstract:Molecular chaperones have evolved to facilitate folding of proteins and RNA in vivo where spontaneous self-assembly is sometimes prohibited. Folding of Tetrahymena ribozyme, assisted by the RNA chaperone CYT-19, surprisingly shows that at physiological Mg2+ ion concentrations, increasing the chaperone concentration reduces the Yield of native ribozymes. In contrast, the more extensively investigated protein chaperone GroEL works in exactly the opposite manner — the Yield of native substrate increases with the increase in chaperone concentration. Thus, the puzzling observation on the assisted ribozyme folding seems to contradict the expectation that a molecular chaperone acts as an efficient annealing machine. We suggest a resolution to this apparently paradoxical behavior by developing a minimal stochastic model that captures the essence of the Iterative Annealing Mechanism (IAM), providing a unified description of chaperone mediated-folding of proteins and RNA. Our theory provides a general relation involving the kinetic rates of the system, which quantitatively predicts how the Yield of native state depends on chaperone concentration. By carefully analyzing a host of experimental data on Tetrahymena (and its mutants) as well as the protein Rubisco and Malate Dehydrogenase, we show that although the Absolute Yield of native states decreases in the ribozyme, the rate of native state production increases in both the cases. By utilizing energy from ATP hydrolysis, both CYT-19 and GroEL drive their substrate concentrations far out of equilibrium, in an endeavor to maximize the native Yield in a short time. Our findings are consistent with the general expectation that proteins or RNA need to be folded by the cellular machinery on biologically relevant timescales, even if the final Yield is lower than what equilibrium thermodynamics would dictate. Besides establishing the IAM as the basis for functions of RNA and protein chaperones, our work shows that cellular copy numbers have been adjusted to optimize the rate of native state production of the folded states of RNA and proteins under physiological conditions.
Changbong Hyeon - One of the best experts on this subject based on the ideXlab platform.
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molecular chaperones maximize the native state Yield on biological times by driving substrates out of equilibrium
Proceedings of the National Academy of Sciences of the United States of America, 2017Co-Authors: Shaon Chakrabarti, Changbong Hyeon, George H Lorimer, D ThirumalaiAbstract:Molecular chaperones facilitate the folding of proteins and RNA in vivo. Under physiological conditions, the in vitro folding of Tetrahymena ribozyme by the RNA chaperone CYT-19 behaves paradoxically; increasing the chaperone concentration reduces the Yield of native ribozymes. In contrast, the protein chaperone GroEL works as expected; the Yield of the native substrate increases with chaperone concentration. The discrepant chaperone-assisted ribozyme folding thus contradicts the expectation that it operates as an efficient annealing machine. To resolve this paradox, we propose a minimal stochastic model based on the Iterative Annealing Mechanism (IAM) that offers a unified description of chaperone-mediated folding of both proteins and RNA. Our theory provides a general relation that quantitatively predicts how the Yield of native states depends on chaperone concentration. Although the Absolute Yield of native states decreases in the Tetrahymena ribozyme, the product of the folding rate and the steady-state native Yield increases in both cases. By using energy from ATP hydrolysis, both CYT-19 and GroEL drive their substrate concentrations far out of equilibrium, thus maximizing the native Yield in a short time. This also holds when the substrate concentration exceeds that of GroEL. Our findings satisfy the expectation that proteins and RNA be folded by chaperones on biologically relevant time scales, even if the final Yield is lower than what equilibrium thermodynamics would dictate. The theory predicts that the quantity of chaperones in vivo has evolved to optimize native state production of the folded states of RNA and proteins in a given time.
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molecular chaperones maximize the native state Yield per unit time by driving substrates out of equilibrium
bioRxiv, 2017Co-Authors: Shaon Chakrabarti, Changbong Hyeon, George H Lorimer, D ThirumalaiAbstract:Molecular chaperones have evolved to facilitate folding of proteins and RNA in vivo where spontaneous self-assembly is sometimes prohibited. Folding of Tetrahymena ribozyme, assisted by the RNA chaperone CYT-19, surprisingly shows that at physiological Mg2+ ion concentrations, increasing the chaperone concentration reduces the Yield of native ribozymes. In contrast, the more extensively investigated protein chaperone GroEL works in exactly the opposite manner — the Yield of native substrate increases with the increase in chaperone concentration. Thus, the puzzling observation on the assisted ribozyme folding seems to contradict the expectation that a molecular chaperone acts as an efficient annealing machine. We suggest a resolution to this apparently paradoxical behavior by developing a minimal stochastic model that captures the essence of the Iterative Annealing Mechanism (IAM), providing a unified description of chaperone mediated-folding of proteins and RNA. Our theory provides a general relation involving the kinetic rates of the system, which quantitatively predicts how the Yield of native state depends on chaperone concentration. By carefully analyzing a host of experimental data on Tetrahymena (and its mutants) as well as the protein Rubisco and Malate Dehydrogenase, we show that although the Absolute Yield of native states decreases in the ribozyme, the rate of native state production increases in both the cases. By utilizing energy from ATP hydrolysis, both CYT-19 and GroEL drive their substrate concentrations far out of equilibrium, in an endeavor to maximize the native Yield in a short time. Our findings are consistent with the general expectation that proteins or RNA need to be folded by the cellular machinery on biologically relevant timescales, even if the final Yield is lower than what equilibrium thermodynamics would dictate. Besides establishing the IAM as the basis for functions of RNA and protein chaperones, our work shows that cellular copy numbers have been adjusted to optimize the rate of native state production of the folded states of RNA and proteins under physiological conditions.
