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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 effect in the steady-state. a Realistic model in which synthesis of both A and B is considered along with their degradation and that of the dimer (upper panel). The lower panels represent the buffering response of heterodimer AB formation to changing the parameter DADB/kAB. For the “normal” conditions, the parameters were: SA = SB = 1nM/min, DA = DB = 0.01 min−1 and kAB ranged from 0.000001 to 1. Here kAB − = 0 because the assembly was considered to be irreversible. The ordinates represent the % of AB when either SA or SB is changed (0.5X or 1.5X) with respect to SA = SB. The results were obtained using equation 1. In such conditions when MPC = DADB/kAB ranges from SA/5 to SA/4 there is maximum buffering for deletions. As discussed in the text, the findings obtained here hold for a reversible situation (only the mathematical expression of the MPC changes). b Buffering response of the heterodimer AB formation to changing SB (as if it varied in a population). As above, SA = 1 and the ratio DADB/kAB = 0.25. The span of the SB values induces a (small) variation of at most 25 % of AB production in any direction with respect to SA = SB = 1nM/min. c Buffering response of heterodimer AB formation to changing DB (as if it varied in a population). As above, kAB = 0.0004 and DA = 0.01. SA = SB = 1nM/min. The span of the DB values displayed induces a maximum decrease of 25 % of AB production with respect to DA = DB = 0.01 min−1
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Fig3: Buffer effect in the steady-state. a Realistic model in which synthesis of both A and B is considered along with their degradation and that of the dimer (upper panel). The lower panels represent the buffering response of heterodimer AB formation to changing the parameter DADB/kAB. For the “normal” conditions, the parameters were: SA = SB = 1nM/min, DA = DB = 0.01 min−1 and kAB ranged from 0.000001 to 1. Here kAB − = 0 because the assembly was considered to be irreversible. The ordinates represent the % of AB when either SA or SB is changed (0.5X or 1.5X) with respect to SA = SB. The results were obtained using equation 1. In such conditions when MPC = DADB/kAB ranges from SA/5 to SA/4 there is maximum buffering for deletions. As discussed in the text, the findings obtained here hold for a reversible situation (only the mathematical expression of the MPC changes). b Buffering response of the heterodimer AB formation to changing SB (as if it varied in a population). As above, SA = 1 and the ratio DADB/kAB = 0.25. The span of the SB values induces a (small) variation of at most 25 % of AB production in any direction with respect to SA = SB = 1nM/min. c Buffering response of heterodimer AB formation to changing DB (as if it varied in a population). As above, kAB = 0.0004 and DA = 0.01. SA = SB = 1nM/min. The span of the DB values displayed induces a maximum decrease of 25 % of AB production with respect to DA = DB = 0.01 min−1

Mentions: 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


Models of buffering of dosage imbalances in protein complexes.

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

Buffer effect in the steady-state. a Realistic model in which synthesis of both A and B is considered along with their degradation and that of the dimer (upper panel). The lower panels represent the buffering response of heterodimer AB formation to changing the parameter DADB/kAB. For the “normal” conditions, the parameters were: SA = SB = 1nM/min, DA = DB = 0.01 min−1 and kAB ranged from 0.000001 to 1. Here kAB − = 0 because the assembly was considered to be irreversible. The ordinates represent the % of AB when either SA or SB is changed (0.5X or 1.5X) with respect to SA = SB. The results were obtained using equation 1. In such conditions when MPC = DADB/kAB ranges from SA/5 to SA/4 there is maximum buffering for deletions. As discussed in the text, the findings obtained here hold for a reversible situation (only the mathematical expression of the MPC changes). b Buffering response of the heterodimer AB formation to changing SB (as if it varied in a population). As above, SA = 1 and the ratio DADB/kAB = 0.25. The span of the SB values induces a (small) variation of at most 25 % of AB production in any direction with respect to SA = SB = 1nM/min. c Buffering response of heterodimer AB formation to changing DB (as if it varied in a population). As above, kAB = 0.0004 and DA = 0.01. SA = SB = 1nM/min. The span of the DB values displayed induces a maximum decrease of 25 % of AB production with respect to DA = DB = 0.01 min−1
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Related In: Results  -  Collection

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Fig3: Buffer effect in the steady-state. a Realistic model in which synthesis of both A and B is considered along with their degradation and that of the dimer (upper panel). The lower panels represent the buffering response of heterodimer AB formation to changing the parameter DADB/kAB. For the “normal” conditions, the parameters were: SA = SB = 1nM/min, DA = DB = 0.01 min−1 and kAB ranged from 0.000001 to 1. Here kAB − = 0 because the assembly was considered to be irreversible. The ordinates represent the % of AB when either SA or SB is changed (0.5X or 1.5X) with respect to SA = SB. The results were obtained using equation 1. In such conditions when MPC = DADB/kAB ranges from SA/5 to SA/4 there is maximum buffering for deletions. As discussed in the text, the findings obtained here hold for a reversible situation (only the mathematical expression of the MPC changes). b Buffering response of the heterodimer AB formation to changing SB (as if it varied in a population). As above, SA = 1 and the ratio DADB/kAB = 0.25. The span of the SB values induces a (small) variation of at most 25 % of AB production in any direction with respect to SA = SB = 1nM/min. c Buffering response of heterodimer AB formation to changing DB (as if it varied in a population). As above, kAB = 0.0004 and DA = 0.01. SA = SB = 1nM/min. The span of the DB values displayed induces a maximum decrease of 25 % of AB production with respect to DA = DB = 0.01 min−1
Mentions: 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

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