Physical constraints on protein structure evolution

Nature has come up with an enormous variety of protein three-dimensional structures, each of which is thought to be optimized for its specific function. A fundamental biological endeavor is to uncover the evolutionary driving forces for discovering and optimizing new folds. A long-standing hypothesis is that fold evolution obeys constraints. Aiming at elucidating those constraints, we evaluated some physical quantities for a large number of biological molecules. Firstly, flexibility was estimated via two independent methods: CONCOORD, which predicts conformational ensembles for atomic protein structures using geometrical constraints, and elastic network models, a simple coarse-grain model. Foldability was measured by Contact Order, which can predict the folding rate of a protein by measuring the distance between native contacts within the protein. Lastly, mechanical strength was predicted with Langevin Dynamics simulations of the conventional Go-type models of proteins, a coarse-grained model based on the X-ray structure, under force. We mapped those physical quantities onto a phylogenomic tree of protein structures resulting from the analysis of the abundance of ~3,000 protein families. Bimodal trends were observed for the different physical quantities suggesting a turnover at around ~1.5 billions years ago. This turnover corresponds to the apparition of multicellular organism that could have drastically modified the constraints applied on the evolution of protein structures. More specifically, before ~1.5 Gya, we observed an increase of foldability and a decrease of mechanical stability that might be the result of a concerted need for fast folders and compact proteins resulting from molecular compartimentalization, i.e. the rise of cells. On the contrary, after ~1.5 Gya, we observed a decrease of foldability and an increase of mechanical stability that suggest a need for mechanical stability probably related to the rise of multicellular organisms with increased mechanical stresses between cells. The loss in foldability after the big bang might be due to that cells started to make use of proteins such as chaperones or other advanced mechanisms thereby removing, at least partly, the constraint for fast folders. Taken together, we identified physical constraints that are likely to play a role in the evolution of protein structures. Our global approach opens avenues for a more comprehensive analysis of genomic and structural data available. Improving our view on protein structure evolution is likely to bring more insights into their functioning. Additionally, it could help constructing a network based view of protein structures evolution improving the classification of the known protein catalogue and aiding the design of new protein structures

Ageing-associated changes in transcriptional elongation influence longevity

Physiological homeostasis becomes compromised during ageing, as a result of impairment of cellular processes, including transcription and RNA splicing1-4. However, the molecular mechanisms leading to the loss of transcriptional fidelity are so far elusive, as are ways of preventing it. Here we profiled and analysed genome-wide, ageing-related changes in transcriptional processes across different organisms: nematodes, fruitflies, mice, rats and humans. The average transcriptional elongation speed (RNA polymerase II speed) increased with age in all five species. Along with these changes in elongation speed, we observed changes in splicing, including a reduction of unspliced transcripts and the formation of more circular RNAs. Two lifespan-extending interventions, dietary restriction and lowered insulin-IGF signalling, both reversed most of these ageing-related changes. Genetic variants in RNA polymerase II that reduced its speed in worms5 and flies6 increased their lifespan. Similarly, reducing the speed of RNA polymerase II by overexpressing histone components, to counter age-associated changes in nucleosome positioning, also extended lifespan in flies and the division potential of human cells. Our findings uncover fundamental molecular mechanisms underlying animal ageing and lifespan-extending interventions, and point to possible preventive measures

Evolutionary Optimization of Protein Folding

<div><p>Nature has shaped the make up of proteins since their appearance, 3.8 billion years ago. However, the fundamental drivers of structural change responsible for the extraordinary diversity of proteins have yet to be elucidated. Here we explore if protein evolution affects folding speed. We estimated folding times for the present-day catalog of protein domains directly from their size-modified contact order. These values were mapped onto an evolutionary timeline of domain appearance derived from a phylogenomic analysis of protein domains in 989 fully-sequenced genomes. Our results show a clear overall increase of folding speed during evolution, with known ultra-fast downhill folders appearing rather late in the timeline. Remarkably, folding optimization depends on secondary structure. While alpha-folds showed a tendency to fold faster throughout evolution, beta-folds exhibited a trend of folding time increase during the last 1.5 billion years that began during the “big bang” of domain combinations. As a consequence, these domain structures are on average slow folders today. Our results suggest that fast and efficient folding of domains shaped the universe of protein structure. This finding supports the hypothesis that optimization of the kinetic and thermodynamic accessibility of the native fold reduces protein aggregation propensities that hamper cellular functions.</p> </div

Change in foldability during evolution for subsets of chain size: Distribution of domain length for domains appearing a) 3.8-1.5 Gya and b) 1.5-0 Gya.

<p>Abundancies were colored according to the average SMCO, the difference between the end points of the polynomial regression of SMCO in this dataset, for the specified initial (a) and later (b) time period. Yellow to red indicates a decrease, and blue an increase in SMCO. The barplots (inset) show the percentage of domains with positive (blue), negative (yellow), and insignificant (green) SMCO.</p

Percentage of all domains with a positive (blue), negative (yellow), and insignificant (green) SMCO.

<p>a) for 3.8-1.5 Gya, and b) 1.5-0 Gya. Each barplot considers one of the four fold classes according to their secondary structure: all-, all-, /, and +, as indicated. The barplots were obtained from domain length distributions analogous to those shown in <a href="http://www.ploscompbiol.org/article/info:doi/10.1371/journal.pcbi.1002861#pcbi.1002861.s003" target="_blank">Figure S3</a>.</p

Protein topologies that favor short range inter-aminoacid contacts might be the result of an evolutionary optimization of foldability and thus would have likely appeared late in evolution.

<p>Protein topologies that favor short range inter-aminoacid contacts might be the result of an evolutionary optimization of foldability and thus would have likely appeared late in evolution.</p