Abstract
BackgroundStoichiometric 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.ResultsWe 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.ConclusionsWe 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.ReviewersThis article was reviewed by Eugene Koonin, Berend Snel and Csaba Pal.
Highlights
Stoichiometric imbalances in macromolecular complexes can lead to altered function
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
Summary
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. Stoichiometric change in a macromolecular complex can induce altered function Subunits of such complexes tend to have similar expression levels, most of the time assessed at the transcriptional level [1, 2]. Monomers in absolute or relative excess can be either not in their final conformation, misfolded or at least expose interfaces, which mediate protein-protein interactions, that should normally be hidden within the complex. Such interfaces tend to be rich in hydrophobic residues that contribute to protein-protein association [9]. This can obviously be the case for overexpressed isolated subunits [11, 12]
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