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Models of buffering of dosage imbalances in protein complexes.

Veitia RA, Birchler JA - Biol. Direct (2015)

Bottom Line: The buffer effect also appears in higher-order structures provided that there are intermediate subcomplexes in the assembly process.We highlight the importance of protein degradation and/or conformational inactivation for buffering to appear.The models sketched here have experimental support but can be further tested with existing biological resources.

View Article: PubMed Central - PubMed

Affiliation: Institut Jacques Monod, 15 rue Hélène Brion, 75013, Paris, France. veitia.reiner@ijm.univ-paris-diderot.fr.

ABSTRACT

Background: Stoichiometric imbalances in macromolecular complexes can lead to altered function. Such imbalances stem from under- or over-expression of a subunit of a complex consequent to a deletion, duplication or regulatory mutation of an allele encoding the relevant protein. In some cases, the phenotypic perturbations induced by such alterations can be subtle or be lacking because nonlinearities in the process of protein complex assembly can provide some degree of buffering.

Results: We explore with biochemical models of increasing plausibility how buffering can be elicited. Specifically, we analyze the formation of a dimer AB and show that there are particular sets of parameters so that decreasing/increasing the input amount of either A or B translates into a non proportional (buffered) change of AB. The buffer effect also appears in higher-order structures provided that there are intermediate subcomplexes in the assembly process.

Conclusions: We highlight the importance of protein degradation and/or conformational inactivation for buffering to appear. The models sketched here have experimental support but can be further tested with existing biological resources.

No MeSH data available.


Related in: MedlinePlus

Buffer effects in the assembly of a heterodimer. a The monomers A and B are involved in competing reactions: their degradation or their dimerization. b Alternative scenario in which both A and B have a preferential conformation to interact with each other (i.e. AI and BI). Conformations AII and BII do not lead to dimers. Note that the parameters of synthesis and degradation encapsulate information on both mRNA and protein in this simplified model, but we assume that no buffering occurs at the transcriptional level. c Buffering response of heterodimer AB formation to changing the input concentration of one monomer. As mentioned in the text, here we consider for simplicity that A and B are synthesized in a very short time scale compared to the rest of the reactions. So we deal with input concentrations and not with parameters of synthesis (as will be the case in Fig. 3). The ordinates represent the % of AB when either A0 or B0 are changed (0.5X or 1.5X, "mutated" condition) with respect to A0 = B0 ("wild-type", wt). The results were obtained with the biochemical simulator GEPASI, which solves numerically the chemical and the underlying differential equations [40]. If normally A0 = B0 = 1nM, DA = DB (here called D) and kAB > > D, at a specific D/kAB value, halving the input amount of either monomer (upper panel) leads to >57 % of dimer in such (rather artificial) conditions of irreversibility. Operating at the same D/kAB value leads to 123 % of AB output when A0 or B0 are increased by 150 %. d Response of heterodimer AB formation to changing the input concentration of one monomer (when one of them can be degraded and the other not). In this case A0 = B0 = 1nM, DA = 0.01 min−1 and DB = 0 min−1
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Fig2: Buffer effects in the assembly of a heterodimer. a The monomers A and B are involved in competing reactions: their degradation or their dimerization. b Alternative scenario in which both A and B have a preferential conformation to interact with each other (i.e. AI and BI). Conformations AII and BII do not lead to dimers. Note that the parameters of synthesis and degradation encapsulate information on both mRNA and protein in this simplified model, but we assume that no buffering occurs at the transcriptional level. c Buffering response of heterodimer AB formation to changing the input concentration of one monomer. As mentioned in the text, here we consider for simplicity that A and B are synthesized in a very short time scale compared to the rest of the reactions. So we deal with input concentrations and not with parameters of synthesis (as will be the case in Fig. 3). The ordinates represent the % of AB when either A0 or B0 are changed (0.5X or 1.5X, "mutated" condition) with respect to A0 = B0 ("wild-type", wt). The results were obtained with the biochemical simulator GEPASI, which solves numerically the chemical and the underlying differential equations [40]. If normally A0 = B0 = 1nM, DA = DB (here called D) and kAB > > D, at a specific D/kAB value, halving the input amount of either monomer (upper panel) leads to >57 % of dimer in such (rather artificial) conditions of irreversibility. Operating at the same D/kAB value leads to 123 % of AB output when A0 or B0 are increased by 150 %. d Response of heterodimer AB formation to changing the input concentration of one monomer (when one of them can be degraded and the other not). In this case A0 = B0 = 1nM, DA = 0.01 min−1 and DB = 0 min−1

Mentions: We will now analyze the assembly of a protein complex, namely the dimer AB, in irreversible conditions, when the amount of one subunit is decreased or increased, according to the reaction scheme represented in Fig. 2a. We focus first on this rather artificial system involving initial fixed amounts of A and B in order to more easily dissect the impact of the competing reactions, namely dimerization and degradation, on the level of buffering. This model would apply, for instance, to a situation in which there is a rapid burst of production of A and B and in which AB is more stable than the free monomers, which might expose degradation signals. Thus, we compare what happens to AB in the WT condition where A0 = B0 (by virtue of ideal dosage balance) to extreme conditions in which the dose of either A or B is increased (1.5x as in an ideal case of a heterozygous gene duplication) or halved (heterozygous deletion). We can also envisage an alternative to protein degradation by supposing that both A and B have a preferential conformation to interact with each other (i.e. AI and BI in Fig. 2b). Indeed, the 3D structure of an isolated monomer can differ from its conformation when it is complexed with binding partners forming an oligomer [18]. This is epitomized by the interactions between domains of the cAMP response element binding protein (CREB-binding protein or CBP) and the activator for thyroid hormone and retinoid receptors (ACTRs) [19]. Both the ACTR and the CBP domains are intrinsically unfolded in isolation but their co-expression leads to a stoichiometric structured complex. Thus, the assembly of a complex may involve unstable intermediates (i.e. “conformational transition states”) that undergo stabilization as oligomerization proceeds. This process has also been termed “interdependent protein dance” [20, 21]. If there is a stoichiometric imbalance, the monomer in excess may have time to transit for a preferred-for-binding to a nonpreferred conformation (inactive for binding). Thus, the steps AI - > AII and BI - > BII in Fig. 2b are formally equivalent to their degradation.Fig. 2


Models of buffering of dosage imbalances in protein complexes.

Veitia RA, Birchler JA - Biol. Direct (2015)

Buffer effects in the assembly of a heterodimer. a The monomers A and B are involved in competing reactions: their degradation or their dimerization. b Alternative scenario in which both A and B have a preferential conformation to interact with each other (i.e. AI and BI). Conformations AII and BII do not lead to dimers. Note that the parameters of synthesis and degradation encapsulate information on both mRNA and protein in this simplified model, but we assume that no buffering occurs at the transcriptional level. c Buffering response of heterodimer AB formation to changing the input concentration of one monomer. As mentioned in the text, here we consider for simplicity that A and B are synthesized in a very short time scale compared to the rest of the reactions. So we deal with input concentrations and not with parameters of synthesis (as will be the case in Fig. 3). The ordinates represent the % of AB when either A0 or B0 are changed (0.5X or 1.5X, "mutated" condition) with respect to A0 = B0 ("wild-type", wt). The results were obtained with the biochemical simulator GEPASI, which solves numerically the chemical and the underlying differential equations [40]. If normally A0 = B0 = 1nM, DA = DB (here called D) and kAB > > D, at a specific D/kAB value, halving the input amount of either monomer (upper panel) leads to >57 % of dimer in such (rather artificial) conditions of irreversibility. Operating at the same D/kAB value leads to 123 % of AB output when A0 or B0 are increased by 150 %. d Response of heterodimer AB formation to changing the input concentration of one monomer (when one of them can be degraded and the other not). In this case A0 = B0 = 1nM, DA = 0.01 min−1 and DB = 0 min−1
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Related In: Results  -  Collection

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Fig2: Buffer effects in the assembly of a heterodimer. a The monomers A and B are involved in competing reactions: their degradation or their dimerization. b Alternative scenario in which both A and B have a preferential conformation to interact with each other (i.e. AI and BI). Conformations AII and BII do not lead to dimers. Note that the parameters of synthesis and degradation encapsulate information on both mRNA and protein in this simplified model, but we assume that no buffering occurs at the transcriptional level. c Buffering response of heterodimer AB formation to changing the input concentration of one monomer. As mentioned in the text, here we consider for simplicity that A and B are synthesized in a very short time scale compared to the rest of the reactions. So we deal with input concentrations and not with parameters of synthesis (as will be the case in Fig. 3). The ordinates represent the % of AB when either A0 or B0 are changed (0.5X or 1.5X, "mutated" condition) with respect to A0 = B0 ("wild-type", wt). The results were obtained with the biochemical simulator GEPASI, which solves numerically the chemical and the underlying differential equations [40]. If normally A0 = B0 = 1nM, DA = DB (here called D) and kAB > > D, at a specific D/kAB value, halving the input amount of either monomer (upper panel) leads to >57 % of dimer in such (rather artificial) conditions of irreversibility. Operating at the same D/kAB value leads to 123 % of AB output when A0 or B0 are increased by 150 %. d Response of heterodimer AB formation to changing the input concentration of one monomer (when one of them can be degraded and the other not). In this case A0 = B0 = 1nM, DA = 0.01 min−1 and DB = 0 min−1
Mentions: We will now analyze the assembly of a protein complex, namely the dimer AB, in irreversible conditions, when the amount of one subunit is decreased or increased, according to the reaction scheme represented in Fig. 2a. We focus first on this rather artificial system involving initial fixed amounts of A and B in order to more easily dissect the impact of the competing reactions, namely dimerization and degradation, on the level of buffering. This model would apply, for instance, to a situation in which there is a rapid burst of production of A and B and in which AB is more stable than the free monomers, which might expose degradation signals. Thus, we compare what happens to AB in the WT condition where A0 = B0 (by virtue of ideal dosage balance) to extreme conditions in which the dose of either A or B is increased (1.5x as in an ideal case of a heterozygous gene duplication) or halved (heterozygous deletion). We can also envisage an alternative to protein degradation by supposing that both A and B have a preferential conformation to interact with each other (i.e. AI and BI in Fig. 2b). Indeed, the 3D structure of an isolated monomer can differ from its conformation when it is complexed with binding partners forming an oligomer [18]. This is epitomized by the interactions between domains of the cAMP response element binding protein (CREB-binding protein or CBP) and the activator for thyroid hormone and retinoid receptors (ACTRs) [19]. Both the ACTR and the CBP domains are intrinsically unfolded in isolation but their co-expression leads to a stoichiometric structured complex. Thus, the assembly of a complex may involve unstable intermediates (i.e. “conformational transition states”) that undergo stabilization as oligomerization proceeds. This process has also been termed “interdependent protein dance” [20, 21]. If there is a stoichiometric imbalance, the monomer in excess may have time to transit for a preferred-for-binding to a nonpreferred conformation (inactive for binding). Thus, the steps AI - > AII and BI - > BII in Fig. 2b are formally equivalent to their degradation.Fig. 2

Bottom Line: The buffer effect also appears in higher-order structures provided that there are intermediate subcomplexes in the assembly process.We highlight the importance of protein degradation and/or conformational inactivation for buffering to appear.The models sketched here have experimental support but can be further tested with existing biological resources.

View Article: PubMed Central - PubMed

Affiliation: Institut Jacques Monod, 15 rue Hélène Brion, 75013, Paris, France. veitia.reiner@ijm.univ-paris-diderot.fr.

ABSTRACT

Background: Stoichiometric imbalances in macromolecular complexes can lead to altered function. Such imbalances stem from under- or over-expression of a subunit of a complex consequent to a deletion, duplication or regulatory mutation of an allele encoding the relevant protein. In some cases, the phenotypic perturbations induced by such alterations can be subtle or be lacking because nonlinearities in the process of protein complex assembly can provide some degree of buffering.

Results: We explore with biochemical models of increasing plausibility how buffering can be elicited. Specifically, we analyze the formation of a dimer AB and show that there are particular sets of parameters so that decreasing/increasing the input amount of either A or B translates into a non proportional (buffered) change of AB. The buffer effect also appears in higher-order structures provided that there are intermediate subcomplexes in the assembly process.

Conclusions: We highlight the importance of protein degradation and/or conformational inactivation for buffering to appear. The models sketched here have experimental support but can be further tested with existing biological resources.

No MeSH data available.


Related in: MedlinePlus