A computational structural study on the DNA-protecting role of the tardigrade-unique Dsup protein

Abstract

the remarkable ability of tardigrades to withstand a wide range of physical and chemical extremes has attracted a considerable interest in these small invertebrates, with a particular focus on the protective roles of proteins expressed during such conditions. the discovery that a tardigrade-unique protein named Dsup (damage suppressor) protects DnA from damage produced by radiation and radicals, has raised expectations concerning its potential applications in biotechnology and medicine. We present in this paper what might be dubbed a "computational experiment" on the Dsup-DnA system. By means of molecular modelling, calculations of electrostatic potentials and electric fields, and all-atom molecular dynamics simulations, we obtained a dynamic picture of the Dsup-DnA interaction. our results suggest that the protein is intrinsically disordered, which enables Dsup to adjust its structure to fit DNA shape. Strong electrostatic attractions and high protein flexibility drive the formation of a molecular aggregate in which Dsup shields DnA. While the precise mechanism of DnA protection conferred by Dsup remains to be elucidated, our study provides some molecular clues of their association that could be of interest for further investigation in this line.

Deep structural insights into RNA‐binding disordered protein regions

“…Such elements, cooperating with neighboring domains are likely important for precise transcription factor binding site specification (Brodsky et al, 2020). In addition, some highly exotic DNA binding proteins, such as the tardigrade DNA damage suppressors (Dsup) might perform dsDNA binding without helical structures (Mínguez‐Toral et al, 2020).…”

Multi-omics Analysis of Dsup Expressing Human Cells Reveals Open Chromatin Architectural Dynamics Underyling Radioprotection

“…In contrast to the hypothesis that introduction of Dsup may perturb the cellular state as an over expression of a chromosomal architectural protein, it may be likely that Dsup just has stronger binding affinity to nucleosomes than HMGN proteins. A recent computational model explored the strong electrostatic interactions and flexibility of Dsup binding with nucleosomal DNA due to its intrinsically disordered structure that allows for tight aggregates to form between Dsup’s highly abundant positive charges in its c-terminus and the negative charges of DNA phosphate backbones 119 . Further in situ or in vitro experiments could elucidate if there is competition for binding sites between these two proteins, and if so the rate of residence on nucleosomes can also be distinguished if in fact Dsup binds stronger of for longer periods of time.…”

Endurance of extremely prolonged nutrient prevention across kingdoms of life

“…Among these stresses, we can find prolonged periods of complete desiccation and starvation, high doses of radiation, and even exposure to outer space ( Jonsson et al., 2019 ; Koshland and Tapia, 2019 ; Weronika and Lukasz, 2017 ). Mechanisms that enable these organisms to survive in stress are being studied, and some interesting unique systems have been discovered, such as the use of intrinsically disordered proteins as a "DNA shield" to protect the genome from desiccation and radiation ( Boothby et al., 2017 ; Minguez-Toral et al., 2020 ). As mentioned, there is no evidence for adaptive genetic mechanisms that operate in tardigrades during stress, but some clues suggest that this is a valid hypothesis.…”