Cage-jump motion reveals universal dynamics and non-universal structural features in glass forming liquids

The sluggish and heterogeneous dynamics of glass forming liquids is frequently associated to the transient coexistence of two phases of particles, respectively with an high and low mobility. In the absence of a dynamical order parameter that acquires a transient bimodal shape, these phases are commonly identified empirically, which makes difficult investigating their relation with the structural properties of the system. Here we show that the distribution of single particle diffusivities can be accessed within a Continuous Time Random Walk description of the intermittent motion, and that this distribution acquires a transient bimodal shape in the deeply supercooled regime, thus allowing for a clear identification of the two coexisting phase. In a simple two-dimensional glass forming model, the dynamic phase coexistence is accompanied by a striking structural counterpart: the distribution of the crystalline-like order parameter becomes also bimodal on cooling, with increasing overlap between ordered and immobile particles. This simple structural signature is absent in other models, such as the three-dimesional Kob-Andersen Lennard-Jones mixture, where more sophisticated order parameters might be relevant. In this perspective, the identification of the two dynamical coexisting phases opens the way to deeper investigations of structure-dynamics correlations.Comment: Published in the J. Stat. Mech. Special Issue "The Role of Structure in Glassy and Jammed Systems

The RNA-Recognition Motifs of TAR DNA-Binding Protein 43 May Play a Role in the Aberrant Self-Assembly of the Protein

The TAR DNA-binding protein 43 (TDP-43) is a nucleic acid-binding protein implicated in gene regulation and RNA processing and shuffling. It is a ribonuclear protein that carries out most of its functions by binding specific nucleic acid sequences with its two RNA-recognition motifs, RRM1 and RRM2. TDP-43 has been identified in toxic cytosolic inclusions in neurodegenerative diseases such as amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration with ubiquitin-positive inclusions (FTLD-U). The unstructured C-terminus has prion-like behavior and has been considered the driver of the aberrant self-assembly of TDP-43. In this work, we set out to test the hypothesis that the RNA-binding domains could also play a role in protein aggregation. This knowledge could be of important value for understanding TDP-43 aberrant, disease-leading behavior and, in the future, inform the design of small molecules that could prevent or slow down protein aggregation by exploiting the RNA-binding properties of the protein. We investigated the behavior of the two tandem RRM domains separately and linked together and studied their self-assembly properties and RNA-binding ability with a number of biophysical techniques. The picture that emerges from our study suggests that this region of the protein plays an important and so far unexplored role in the aggregation of this protein

Symmetric Key Structural Residues in Symmetric Proteins with Beta-Trefoil Fold

To understand how symmetric structures of many proteins are formed from asymmetric sequences, the proteins with two repeated beta-trefoil domains in Plant Cytotoxin B-chain family and all presently known beta-trefoil proteins are analyzed by structure-based multi-sequence alignments. The results show that all these proteins have similar key structural residues that are distributed symmetrically in their structures. These symmetric key structural residues are further analyzed in terms of inter-residues interaction numbers and B-factors. It is found that they can be distinguished from other residues and have significant propensities for structural framework. This indicates that these key structural residues may conduct the formation of symmetric structures although the sequences are asymmetric

The cold denaturation of IscU highlights structure–function dualism in marginally stable proteins

Proteins undergo both cold and heat denaturation, but often cold denaturation cannot be detected because it occurs at temperatures below water freezing. Proteins undergoing detectable cold as well as heat denaturation yield a reliable curve of protein stability. Here we use bacterial IscU, an essential and ancient protein involved in iron cluster biogenesis, to show an important example of unbiased cold denaturation, based on electrostatic frustration caused by a dualism between iron–sulfur cluster binding and the presence of a functionally essential electrostatic gate. We explore the structural determinants and the universals that determine cold denaturation with the aid of a coarse grain model. Our results set a firm point in our understanding of cold denaturation and give us general rules to induce and predict protein cold denaturation. The conflict between ligand binding and stability hints at the importance of the structure–function dualism in protein evolution. Proteins can undergo both heat and cold denaturation, and in marginally stable proteins this is often controlled by electrostatic frustration. Here, the authors find that residues essential for protein function are also structural determinants for cold denaturation

Towards a metabolomic approach to investigate iron-sulfur cluster biogenesis

Iron–sulfur clusters are prosthetic groups that are assembled on their acceptor proteins through a complex machine centered on a desulfurase enzyme and a transient scaffold protein. Studies to establish the mechanism of cluster formation have so far used either in vitro or in vivo methods, which have often resulted in contrasting or non‐comparable results. We suggest, here, an alternative approach to study the enzymatic reaction, that is based on the combination of genetically engineered bacterial strains depleted of specific components, and the detection of the enzymatic kinetics in cellular extracts through metabolomics. Our data prove that this ex vivo approach closely reproduces the in vitro results while retaining the full complexity of the system. We demonstrate that co‐presence of bacterial frataxin and iron is necessary to observe an inhibitory effect of the enzymatic activity of bacterial frataxin. Our approach provides a new powerful tool for the study of iron–sulfur cluster biogenesis

The seesaw between normal function and protein aggregation: How functional interactions may increase protein solubility

AbstractProtein aggregation has been studied for at least 3 decades, and many of the principles that regulate this event are relatively well understood. Here, however, we present a different perspective to explain why proteins aggregate: we argue that aggregation may occur as a side‐effect of the lack of one or more natural partners that, under physiologic conditions, would act as chaperones. This would explain why the same surfaces that have evolved for functional purposes are also those that favour aggregation. In the course of reviewing this field, we substantiate our hypothesis with three paradigmatic examples that argue for the generality of our proposal. An obvious corollary of this hypothesis is, of course, that targeting the physiological partners of a protein could be the most direct and specific approach to designing anti‐aggregation molecules. Our analysis may thus inform a different strategy for combating diseases of protein aggregation and misfolding