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A gourd becomes useful only after it has been emptied. For then its dry rind may serve as a container. The same goes for us, magistrate. It's only after we have been emptied of all our vain hopes, all our petty desires and cherished illusions, that we can be usuful to others.

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Robert van GULIK


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Flexibility provides an efficient epigenetic way to manage risk

This page presents a summary of an article dedicated to the memory of Jean Fourmentin and published in the journal Genes, which aims to propose a conjecture on some processes that might underlie the transition from ageing to senescence. A popularised version of this opinion was published in Project Syndicate.

The notion of antifragility, an attribute of systems that that allows them to thrive under varying conditions, has been proposed by Nassim Taleb in a business context. This idea requires these systems to tinker, that is, to respond creatively to changes in their environment. Evolution induced by natural selection is a fairly obvious example. In this ubiquitous process, an original entity, challenged by a constantly changing environment, creates variants that evolve into new entities. Analysis of the functions essential to the steady state of life provides examples of entities that can be antifragile. One of these is proteins with flexible regions that can undergo functional modifications of their side residues or backbone and thus implement the bricolage (tinkering) that leads to antifragility. This intrinsic property of the cellular framework must be taken into account when considering the construction of cellular factories based on engineering principles.

Long and short proteins make up the stationary essential proteome, but proteins of average length do not

The distribution of the length of the proteins important for stationary survival is compared in Figure 1 to that of all proteins in the E. coli proteome: it displays a remarkable bias both for short and long proteins. Briefly, there is an excess in short proteins (which is understandable as they should undergo less accidents during their synthesis) and long or very long proteins (which is a surprise).

histogram

Long proteins are generally multi-domain proteins connected by flexible links. However, in addition to being more flexible, long proteins have remarkable structural features. Long proteins can fulfil the unfolding and misfolding stability conditions more easily than short ones, as they have a higher number of native interactions per residue. They are also relatively enriched in small amino acid residues. In addition, there is a correlation between the tendency to fold and the hydrophobicity of the proteins, with long proteins being less hydrophobic than short ones. Interestingly, when hydrophobicity is low, long proteins are more resistant to unfolding and misfolding than short proteins. Collapse of unfolded polypeptides, generally thought to be due to hydrophobic forces, is an early event in protein folding. Whether hydrogen bonds and side chains play an important role in this process remains an open question. This question has recently been addressed by showing that the backbone plays a considerable organising role. It therefore seems important that flexibility is an essential feature of proteins involved in stationary conditions. Before discussing further how antifragility can exploit flexibility, we explore some features of flexible regions, which could be a selected trait in proteins that have to solve new functional questions during aging.

Birth, growth, maturation and senescence are the four ages of all cells. The same applies to their components. In general, the maturation stage is ignored: it is considered that the components of the cell are synthesised, used in their final form, and then decompose and are either repaired or destroyed. Maturation and possible functional improvement during ageing are rarely taken into account. Senescence and ageing are considered equivalent. Yet many physico-chemical processes suggest that the state of cellular components at a given time should be considered as actively evolving through a series of ageing states. In fact, regardless of apoptosis (which may be a process of resetting the system to its ground state), most cells harbour a mixture of young and old components, reflecting their overall division history

ageing

Flexibility plays an important role here. We are exploring the notion that, before the deleterious process of senescence is triggered, a maturation process will create a population of molecules that will experience different fates. In some cases, the flexible regions will make the protein susceptible to degradation by proteolytic systems. In other cases, via interaction with specific partners, they will distribute the protein among functional entities. Finally, in the face of a variety of challenges, flexibility could discover new properties of the protein that need time to be implemented. Thus, different individuals in a collection of a given gene product may have different fates and respond differently to similar challenges.