Abstract
The proteome of the radiation- and desiccation-resistant bacterium D. radiodurans features a group of proteins that contain significant intrinsically disordered regions that are not present in non-extremophile homologues. Interestingly, this group includes a number of housekeeping and repair proteins such as DNA polymerase III, nudix hydrolase and rotamase. Here, we focus on a member of the nudix hydrolase family from D. radiodurans possessing low-complexity N- and C-terminal tails, which exhibit sequence signatures of intrinsic disorder and have unknown function. The enzyme catalyzes the hydrolysis of oxidatively damaged and mutagenic nucleotides, and it is thought to play an important role in D. radiodurans during the recovery phase after exposure to ionizing radiation or desiccation. We use molecular dynamics simulations to study the dynamics of the protein, and study its hydration free energy using the GB/SA formalism. We show that the presence of disordered tails significantly decreases the hydration free energy of the whole protein. We hypothesize that the tails increase the chances of the protein to be located in the remaining water patches in the desiccated cell, where it is protected from the desiccation effects and can function normally. We extrapolate this to other intrinsically disordered regions in proteins, and propose a novel function for them: intrinsically disordered regions increase the “surface-properties” of the folded domains they are attached to, making them on the whole more hydrophilic and potentially influencing, in this way, their localization and cellular activity.
Highlights
The dominant paradigm for describing the functioning of proteins is that of well-defined, structured molecular machines undergoing concerted, conformational changes while carrying out their function [1,2,3]
The results presented in this paper show on several levels a correlation between the N and C-terminal tails’ presence and an increased hydrophilicity of nudix hydrolase in D. radiodurans
The results of the hydration free energy calculations show an even clearer picture: the hydration free energy of DRNH is twice as large as an average protein’s hydration free energy, with the tails contributing the major part to this difference
Summary
The dominant paradigm for describing the functioning of proteins is that of well-defined, structured molecular machines undergoing concerted, conformational changes while carrying out their function [1,2,3]. Over the past few years it has become clear that the reality is much more complex, and that there are proteins that do not have a defined tertiary structure, and yet still carry out multitudes of different important functions These intrinsically disordered proteins and protein segments (IDPs), called ‘‘natively unfolded’’ or ‘‘natively disordered’’, are by definition difficult to study using classical methods of structural biology, but they have in recent years received significant attention, largely due to two facts [4,5,6,7,8,9,10,11,12,13,14]. These numbers are large: even if some of the predicted disordered regions prove to be structured, it is likely that IDPs in eukaryotes by far exceed, for example, the entire population of membrane proteins
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