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Tandem Domains with Tuned Interactions Are a Powerful Biological Design Principle.

Nussinov R, Tsai CJ - PLoS Biol. (2015)

Bottom Line: Allosteric effects of mutations, ligand binding, or post-translational modifications on protein function occur through changes to the protein's shape, or conformation.In a new PLOS Biology paper, Melacini and colleagues describe a novel model of protein regulation, the "Double-Conformational Selection Model", which demonstrates how two tandem ligand-binding domains interact to regulate protein function.Here we explain how tandem domains with tuned interactions-but not single domains-can provide a blueprint for sensitive activation sensors within a narrow window of ligand concentration, thereby promoting signaling control.

View Article: PubMed Central - PubMed

Affiliation: Cancer and Inflammation Program, Leidos Biomedical Research, Inc., Frederick, Maryland, United States of America.

ABSTRACT
Allosteric effects of mutations, ligand binding, or post-translational modifications on protein function occur through changes to the protein's shape, or conformation. In a cell, there are many copies of the same protein, all experiencing these perturbations in a dynamic fashion and fluctuating through different conformations and activity states. According to the "conformational selection and population shift" theory, ligand binding selects a particular conformation. This perturbs the ensemble and induces a population shift. In a new PLOS Biology paper, Melacini and colleagues describe a novel model of protein regulation, the "Double-Conformational Selection Model", which demonstrates how two tandem ligand-binding domains interact to regulate protein function. Here we explain how tandem domains with tuned interactions-but not single domains-can provide a blueprint for sensitive activation sensors within a narrow window of ligand concentration, thereby promoting signaling control.

Show MeSH
How the tandem CBDs in the PKA regulatory subunit adjust PKA’s activity as a cellular switch through the binding of second messenger cAMP.An ideal biological switch, here in the case of PKA activity as a function of cAMP concentration, is to establish a lower transition concentration (indicated by the red arrows at a middle point of maximum and minimum activity of PKA) and a narrow transition window (indicated by the length of blue horizontal lines) that passes the transition point and ends without a significant change of PKA activity with respect to cAMP concentration change. The orange transition curve on the right corresponds to a scenario where PKA regulatory subunit has only a single CBD. Both green and red transition curves are for PKA regulatory subunit with tandem CBDs; but the green curve does not have a significant population of the closed form with cAMP-bound CBDs (illustrated in Fig 1), as in the case of the W260 mutant. In the scenario depicted by the orange curve with a single CBD, the activity of PKA is proportional to [CBDactive] + [CBD(cAMP)] / [CBDinactive] + [CBDactive] + [CBD(cAMP)] if we assume that cAMP-bound CBD dominates the active conformation. The corresponding graphic presentation is given on the top right with orange divider line with individual species illustrated in Fig 1. In the scenario referred to by the green curve, PKA activity is proportional to the middle graphic presentation with the green divider. However, with the closed form, PKA activity shown by the red curve corresponds to the bottom graphic presentation with red divider. Note that this is only a schematic figure for clarity and only representative states are shown in the cartoons in the right side of the figure. As in the case of the tandem domains only the inactive–inactive state is explicitly shown for the apo form. For a full enumeration of states, see Fig 1A.
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pbio.1002306.g002: How the tandem CBDs in the PKA regulatory subunit adjust PKA’s activity as a cellular switch through the binding of second messenger cAMP.An ideal biological switch, here in the case of PKA activity as a function of cAMP concentration, is to establish a lower transition concentration (indicated by the red arrows at a middle point of maximum and minimum activity of PKA) and a narrow transition window (indicated by the length of blue horizontal lines) that passes the transition point and ends without a significant change of PKA activity with respect to cAMP concentration change. The orange transition curve on the right corresponds to a scenario where PKA regulatory subunit has only a single CBD. Both green and red transition curves are for PKA regulatory subunit with tandem CBDs; but the green curve does not have a significant population of the closed form with cAMP-bound CBDs (illustrated in Fig 1), as in the case of the W260 mutant. In the scenario depicted by the orange curve with a single CBD, the activity of PKA is proportional to [CBDactive] + [CBD(cAMP)] / [CBDinactive] + [CBDactive] + [CBD(cAMP)] if we assume that cAMP-bound CBD dominates the active conformation. The corresponding graphic presentation is given on the top right with orange divider line with individual species illustrated in Fig 1. In the scenario referred to by the green curve, PKA activity is proportional to the middle graphic presentation with the green divider. However, with the closed form, PKA activity shown by the red curve corresponds to the bottom graphic presentation with red divider. Note that this is only a schematic figure for clarity and only representative states are shown in the cartoons in the right side of the figure. As in the case of the tandem domains only the inactive–inactive state is explicitly shown for the apo form. For a full enumeration of states, see Fig 1A.

Mentions: As shown by Fig 1, binding of cAMP changes the picture. Selected primarily by an active conformation of CBD-B—since the affinity of CBD-B to cAMP is higher than that of CBD-A—the binding shifts the RAB equilibrium. Even though binding to CBD-A can already lower the constant for the cAMP-dependent activation (Ka) of PKA (Fig 2), the binding of the CBD-B and association of the two domains explains the cAMP-dependent activation of PKA by more than an order of magnitude from 1 μM to 80 nM [6].


Tandem Domains with Tuned Interactions Are a Powerful Biological Design Principle.

Nussinov R, Tsai CJ - PLoS Biol. (2015)

How the tandem CBDs in the PKA regulatory subunit adjust PKA’s activity as a cellular switch through the binding of second messenger cAMP.An ideal biological switch, here in the case of PKA activity as a function of cAMP concentration, is to establish a lower transition concentration (indicated by the red arrows at a middle point of maximum and minimum activity of PKA) and a narrow transition window (indicated by the length of blue horizontal lines) that passes the transition point and ends without a significant change of PKA activity with respect to cAMP concentration change. The orange transition curve on the right corresponds to a scenario where PKA regulatory subunit has only a single CBD. Both green and red transition curves are for PKA regulatory subunit with tandem CBDs; but the green curve does not have a significant population of the closed form with cAMP-bound CBDs (illustrated in Fig 1), as in the case of the W260 mutant. In the scenario depicted by the orange curve with a single CBD, the activity of PKA is proportional to [CBDactive] + [CBD(cAMP)] / [CBDinactive] + [CBDactive] + [CBD(cAMP)] if we assume that cAMP-bound CBD dominates the active conformation. The corresponding graphic presentation is given on the top right with orange divider line with individual species illustrated in Fig 1. In the scenario referred to by the green curve, PKA activity is proportional to the middle graphic presentation with the green divider. However, with the closed form, PKA activity shown by the red curve corresponds to the bottom graphic presentation with red divider. Note that this is only a schematic figure for clarity and only representative states are shown in the cartoons in the right side of the figure. As in the case of the tandem domains only the inactive–inactive state is explicitly shown for the apo form. For a full enumeration of states, see Fig 1A.
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pbio.1002306.g002: How the tandem CBDs in the PKA regulatory subunit adjust PKA’s activity as a cellular switch through the binding of second messenger cAMP.An ideal biological switch, here in the case of PKA activity as a function of cAMP concentration, is to establish a lower transition concentration (indicated by the red arrows at a middle point of maximum and minimum activity of PKA) and a narrow transition window (indicated by the length of blue horizontal lines) that passes the transition point and ends without a significant change of PKA activity with respect to cAMP concentration change. The orange transition curve on the right corresponds to a scenario where PKA regulatory subunit has only a single CBD. Both green and red transition curves are for PKA regulatory subunit with tandem CBDs; but the green curve does not have a significant population of the closed form with cAMP-bound CBDs (illustrated in Fig 1), as in the case of the W260 mutant. In the scenario depicted by the orange curve with a single CBD, the activity of PKA is proportional to [CBDactive] + [CBD(cAMP)] / [CBDinactive] + [CBDactive] + [CBD(cAMP)] if we assume that cAMP-bound CBD dominates the active conformation. The corresponding graphic presentation is given on the top right with orange divider line with individual species illustrated in Fig 1. In the scenario referred to by the green curve, PKA activity is proportional to the middle graphic presentation with the green divider. However, with the closed form, PKA activity shown by the red curve corresponds to the bottom graphic presentation with red divider. Note that this is only a schematic figure for clarity and only representative states are shown in the cartoons in the right side of the figure. As in the case of the tandem domains only the inactive–inactive state is explicitly shown for the apo form. For a full enumeration of states, see Fig 1A.
Mentions: As shown by Fig 1, binding of cAMP changes the picture. Selected primarily by an active conformation of CBD-B—since the affinity of CBD-B to cAMP is higher than that of CBD-A—the binding shifts the RAB equilibrium. Even though binding to CBD-A can already lower the constant for the cAMP-dependent activation (Ka) of PKA (Fig 2), the binding of the CBD-B and association of the two domains explains the cAMP-dependent activation of PKA by more than an order of magnitude from 1 μM to 80 nM [6].

Bottom Line: Allosteric effects of mutations, ligand binding, or post-translational modifications on protein function occur through changes to the protein's shape, or conformation.In a new PLOS Biology paper, Melacini and colleagues describe a novel model of protein regulation, the "Double-Conformational Selection Model", which demonstrates how two tandem ligand-binding domains interact to regulate protein function.Here we explain how tandem domains with tuned interactions-but not single domains-can provide a blueprint for sensitive activation sensors within a narrow window of ligand concentration, thereby promoting signaling control.

View Article: PubMed Central - PubMed

Affiliation: Cancer and Inflammation Program, Leidos Biomedical Research, Inc., Frederick, Maryland, United States of America.

ABSTRACT
Allosteric effects of mutations, ligand binding, or post-translational modifications on protein function occur through changes to the protein's shape, or conformation. In a cell, there are many copies of the same protein, all experiencing these perturbations in a dynamic fashion and fluctuating through different conformations and activity states. According to the "conformational selection and population shift" theory, ligand binding selects a particular conformation. This perturbs the ensemble and induces a population shift. In a new PLOS Biology paper, Melacini and colleagues describe a novel model of protein regulation, the "Double-Conformational Selection Model", which demonstrates how two tandem ligand-binding domains interact to regulate protein function. Here we explain how tandem domains with tuned interactions-but not single domains-can provide a blueprint for sensitive activation sensors within a narrow window of ligand concentration, thereby promoting signaling control.

Show MeSH