Learning to read and write in evolution: from static pseudoenzymes and pseudosignalers to dynamic gear shifters

Abstract

We present a systems biology view on pseudoenzymes that acknowledges that genes are not selfish: the genome is. With network function as the selectable unit, there has been an evolutionary bonus for recombination of functions of and within proteins. Many proteins house a functionality by which they 'read' the cell's state, and one by which they 'write' and thereby change that state. Should the writer domain lose its cognate function, a 'pseudoenzyme' or 'pseudosignaler' arises. GlnK involved in ammonia assimilation may well be a pseudosignaler, associating 'reading' the nitrogen state of the cell to 'writing' the ammonium uptake activity. We identify functional pseudosignalers in the cyclin-dependent kinase complexes regulating cell-cycle progression. For the mitogen-activated protein kinase pathway, we illustrate how a 'dead' pseudosignaler could produce potentially selectable functionalities. Four billion years ago, bioenergetics may have shuffled 'electron-writers', producing various networks that all served the same function of anaerobic ATP synthesis and carbon assimilation from hydrogen and carbon dioxide, but at different ATP/acetate ratios. This would have enabled organisms to deal with variable challenges of energy need and substrate supply. The same principle might enable 'gear-shifting' in real time, by dynamically generating different pseudo-redox enzymes, reshuffling their coenzymes, and rerouting network fluxes. Non-stationary pH gradients in thermal vents together with similar such shuffling mechanisms may have produced a first selectable proton-motivated pyrophosphate synthase and subsequent ATP synthase. A combination of functionalities into enzymes, signalers, and the pseudo-versions thereof may offer fitness in terms of plasticity, both in real time and in evolution.

Clb3-centered regulations are recurrent across distinct parameter regions in minimal autonomous cell cycle oscillator designs

“…For example, in our cell cycle networks, binding or phosphorylation affinity of the Clb/Cdk1 complexes could be altered. Consequently, cells may theoretically be able to dynamically shift network configurations, as we have proposed for metabolic networks 70,71 , causing switches in phenotype. Our results indicate that, if these changes occur within the core cell cycle regulatory network, an impact on the ability of the network to exhibit oscillations can be observed.…”

Pseudophosphatase MK‐STYX: the atypical member of the MAP kinase phosphatases

“…Almost a quarter of a century later, pseudophosphatases and pseudoenzymes, in general, are receiving well‐deserved attention and categorization of these molecules as integral regulatory components of signaling pathways. Through genomic analysis, it became apparent that pseudoenzymes are widespread [2,5,10,14,77], and it thus became important to understand more of their actions [1,4,10]. This review detailed substantial and compelling evidence that one such protein, MK‐STYX, is a critical signaling regulator of signaling pathways such as apoptosis, stress response, RhoA, and neuronal differentiation [4,13,27–29,42,70].…”

“…The evolutionary conservation of these catalytically inactive homologs and their widespread existence (they can be found among the bacterial luciferases, bacterial and eukaryotic kinases, phosphatases, proteases, GTPases, synthetases, etc.) underlines the importance of understanding their functions [2,4,5]. Although use of the ‘pseudo’ prefix inhibited their investigation for many years, by implying a lack of function, in the past ten years, they have become appreciated and viewed as relevant and important signaling molecules—highlighting the necessity of this special issue on pseudoenzymes.…”

Gear Shifting in Biological Energy Transduction

“…Living organisms may exhibit similar gear shifting. Clostridium ljungdahlii, for instance, contains alternatives in its genome of redox reactions that produce different ATP/acetate ratios and have been proposed to mediate gear shifting [22]. Paracoccus denitrificans and Escherichia coli avail themselves of various terminal oxidases enabling gear shifting in their proton pumping activity [23,24].…”