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Abstract Intrinsically disordered proteins and protein regions (IDPs) are prevalent in all proteomes and are essential to cellular function. Unlike folded proteins, IDPs exist in an ensemble of dissimilar conformations. Despite this structural plasticity, intramolecular interactions create sequence-specific structural biases that determine an IDP ensemble’s three-dimensional shape. Such structural biases can be key to IDP function and are often measured in vitro, but whether those biases are preserved inside the cell is unclear. Here we show that structural biases in IDP ensembles found in vitro are recapitulated inside human-derived cells. We further reveal that structural biases can change in a sequence-dependent manner due to changes in the intracellular milieu, subcellular localization, and intramolecular interactions with tethered well-folded domains. We propose that the structural sensitivity of IDP ensembles can be leveraged for biological function, can be the underlying cause of IDP-driven pathology or can be used to design disorder-based biosensors and actuators. 

The molecular machinery that enables life has evolved in water, yet many of the organisms around us are able to survive even extreme desiccation. Especially remarkable are single-cell and sedentary organisms that rely on specialized biomolecular machinery to survive in environments that are routinely subjected to a near-complete lack of water. In this review, we zoom in on the molecular level of what is happening in the cellular environment under water stress. We cover the various mechanisms by which biochemical components of the cell can dysfunction in dehydrated cells and detail the different strategies that organisms have evolved to eliminate or cope with these desiccation-induced perturbations. We specifically focus on two survival strategies: (1) the use of disordered proteins to protect the cellular environment before, during, and in the recovery from desiccation, and (2) the use of biomolecular condensates as a self-assembly mechanism that can sequester or protect specific cellular machinery in times of water stress. We provide a summary of experimental work describing the critical contributions of disordered proteins and biomolecular condensates to the cellular response to water loss and highlight their role in desiccation tolerance. Desiccation biology is an exciting area of cell biology, still far from being completely explored. Understanding it on the molecular level is bound to give us critical new insights in how life adapted/can adapt to the loss of water, spanning from the early colonization of land to how we can deal with climate change in our future.