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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

Complex topology and dosage sensitivity. a Case of a trimer in which the green subunit is a bridge. Halving of the latter leads to halving trimer output. However, halving the amounts of the orange subunits can lead to as low as 25 % of trimer. Overexpression of the orange subunits can be inconsequential from the perspective of the trimer output but entails a futile cost, whereas overexpression of the green ones leads to a titration effect (formation of dimeric subcomplexes), which reduces trimer output. b When the orange  subunits can, for instance, preassemble, halving their amount translates into a proportional decrease of trimer and the increase of the green  ones does not alter the amount of trimer. This shows how the topology of the complex and not only its composition modulate dosage sensitivity
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Fig1: Complex topology and dosage sensitivity. a Case of a trimer in which the green subunit is a bridge. Halving of the latter leads to halving trimer output. However, halving the amounts of the orange subunits can lead to as low as 25 % of trimer. Overexpression of the orange subunits can be inconsequential from the perspective of the trimer output but entails a futile cost, whereas overexpression of the green ones leads to a titration effect (formation of dimeric subcomplexes), which reduces trimer output. b When the orange  subunits can, for instance, preassemble, halving their amount translates into a proportional decrease of trimer and the increase of the green  ones does not alter the amount of trimer. This shows how the topology of the complex and not only its composition modulate dosage sensitivity

Mentions: To gain insight into the biochemical bases of the effects of stoichiometric imbalances, we explore the consequences of under- or over-expression of a subunit of a complex due, for instance, to a deletion, duplication or regulatory mutation of an allele encoding the relevant protein in a diploid organism. In such cases there is an imbalance that increases the concentration of unpartnered subunits. The deficit of one binding partner leaves the remaining partners in (relative) excess. When this situation engenders a dominant phenotype we speak of haploinsufficiency (HI). The molecular bases of HI can be diverse, depending on the systems under consideration [5]. In the case of macromolecular complexes, the explanation of some cases of HI is almost intuitive. For instance, if the complex is a trimer that contains 2 molecules of A and one molecule of B, the effect of a decrease in the concentration of A is probably more dramatic than for B, as shown in Fig. 1. However, as also shown in this figure, the result depends on the topology of the complexes [5, 6]. These examples epitomize why the expression levels of the subunits of a complex evolve to be co-regulated. Although most of what follows focuses on situations arising in diploid organisms, it is worth saying that the dosage balance principles hold also for prokaryotes. Indeed, a systematically analysis of macromolecular complexes from E. coli has shown that more than half of the relevant molecules are synthesized at levels (counted as molecules per generation) very well correlated with their stoichiometry within the complexes [7]. This proportional synthesis out of a polycistron relies on translational tuning [7, 8]. Not surprisingly, similar results have been found for stable complexes from S. cerevisiae [7].Fig. 1


Models of buffering of dosage imbalances in protein complexes.

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

Complex topology and dosage sensitivity. a Case of a trimer in which the green subunit is a bridge. Halving of the latter leads to halving trimer output. However, halving the amounts of the orange subunits can lead to as low as 25 % of trimer. Overexpression of the orange subunits can be inconsequential from the perspective of the trimer output but entails a futile cost, whereas overexpression of the green ones leads to a titration effect (formation of dimeric subcomplexes), which reduces trimer output. b When the orange  subunits can, for instance, preassemble, halving their amount translates into a proportional decrease of trimer and the increase of the green  ones does not alter the amount of trimer. This shows how the topology of the complex and not only its composition modulate dosage sensitivity
© Copyright Policy - open-access
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC4537584&req=5

Fig1: Complex topology and dosage sensitivity. a Case of a trimer in which the green subunit is a bridge. Halving of the latter leads to halving trimer output. However, halving the amounts of the orange subunits can lead to as low as 25 % of trimer. Overexpression of the orange subunits can be inconsequential from the perspective of the trimer output but entails a futile cost, whereas overexpression of the green ones leads to a titration effect (formation of dimeric subcomplexes), which reduces trimer output. b When the orange  subunits can, for instance, preassemble, halving their amount translates into a proportional decrease of trimer and the increase of the green  ones does not alter the amount of trimer. This shows how the topology of the complex and not only its composition modulate dosage sensitivity
Mentions: To gain insight into the biochemical bases of the effects of stoichiometric imbalances, we explore the consequences of under- or over-expression of a subunit of a complex due, for instance, to a deletion, duplication or regulatory mutation of an allele encoding the relevant protein in a diploid organism. In such cases there is an imbalance that increases the concentration of unpartnered subunits. The deficit of one binding partner leaves the remaining partners in (relative) excess. When this situation engenders a dominant phenotype we speak of haploinsufficiency (HI). The molecular bases of HI can be diverse, depending on the systems under consideration [5]. In the case of macromolecular complexes, the explanation of some cases of HI is almost intuitive. For instance, if the complex is a trimer that contains 2 molecules of A and one molecule of B, the effect of a decrease in the concentration of A is probably more dramatic than for B, as shown in Fig. 1. However, as also shown in this figure, the result depends on the topology of the complexes [5, 6]. These examples epitomize why the expression levels of the subunits of a complex evolve to be co-regulated. Although most of what follows focuses on situations arising in diploid organisms, it is worth saying that the dosage balance principles hold also for prokaryotes. Indeed, a systematically analysis of macromolecular complexes from E. coli has shown that more than half of the relevant molecules are synthesized at levels (counted as molecules per generation) very well correlated with their stoichiometry within the complexes [7]. This proportional synthesis out of a polycistron relies on translational tuning [7, 8]. Not surprisingly, similar results have been found for stable complexes from S. cerevisiae [7].Fig. 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