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Heat stress can cause cell death by triggering the aggregation of essential proteins. In bacteria, aggregated proteins are rescued by the canonical Hsp70/AAA+ (ClpB) bi-chaperone disaggregase. Man-made, severe stress conditions applied during, e.g., food processing represent a novel threat for bacteria by exceeding the capacity of the Hsp70/ClpB system. Here, we report on the potent autonomous AAA+ disaggregase ClpL from Listeria monocytogenes that provides enhanced heat resistance to the food-borne pathogen enabling persistence in adverse environments. ClpL shows increased thermal stability and enhanced disaggregation power compared to Hsp70/ClpB, enabling it to withstand severe heat stress and to solubilize tight aggregates. ClpL binds to protein aggregates via aromatic residues present in its N-terminal domain (NTD) that adopts a partially folded and dynamic conformation. Target specificity is achieved by simultaneous interactions of multiple NTDs with the aggregate surface. ClpL shows remarkable structural plasticity by forming diverse higher assembly states through interacting ClpL rings. NTDs become largely sequestered upon ClpL ring interactions. Stabilizing ring assemblies by engineered disulfide bonds strongly reduces disaggregation activity, suggesting that they represent storage states.

Abstract The RNA-binding motif protein RBM5 belongs to a family of multi-domain RNA binding proteins that regulate alternative splicing of genes important for apoptosis and cell proliferation and have been implicated in cancer. RBM5 harbors structural modules for RNA recognition, such as RRM domains and a Zn finger, and protein-protein interactions such as an OCRE domain. Here, we characterize binding of the RBM5 RRM1-ZnF1-RRM2 domains to cis-regulatory RNA elements. A structure of the RRM1-ZnF1 region in complex with RNA shows how the tandem domains cooperate to sandwich target RNA and specifically recognize a GG dinucleotide in a non-canonical fashion. While the RRM1-ZnF1 domains act as a single structural module, RRM2 is connected by a flexible linker and tumbles independently. However, all three domains participate in RNA binding and adopt a closed architecture upon RNA binding. Our data highlight how cooperativity and conformational modularity of multiple RNA binding domains enable the recognition of distinct RNA motifs, thereby contributing to the regulation of alternative splicing. Remarkably, we observe surprising differences in coupling of the RNA binding domains between the closely related homologs RBM5 and RBM10.

Here the authors show how the MTREC core protein Red1 binds to and sequesters Pla1 from the 3’-end processing machinery to hyperadenylate cryptic unstable transcripts and target them to the exosome for efficient degradation.

Several areas of wireless networking, such as wireless sensor networks or the Internet of Things, require application data to be distributed to multiple receivers in an area beyond the transmission range of a single node. This can be achieved by using the wireless medium’s broadcast property when retransmitting data. Due to the energy constraints of typical wireless devices, a broadcasting scheme that consumes as little energy as possible is highly desirable. In this article, we present a novel multi-hop data dissemination protocol called BTP. It uses a game-theoretical model to construct a spanning tree in a decentralized manner to minimize the total energy consumption of a network by minimizing the transmission power of each node. Although BTP is based on a game-theoretical model, it neither requires information exchange between distant nodes nor time synchronization during its operation, and it inhibits graph cycles effectively. The protocol is evaluated in Matlab and NS-3 simulations and through real-world implementation on a testbed of 75 Raspberry Pis. The evaluation conducted shows that our proposed protocol can achieve a total energy reduction of up to 90% compared to a simple broadcast protocol in real-world experiments.

The SRP Alu domain is involved in co-translational protein targeting. Soni et al. investigate the Alu domain of Plasmodium falciparum, the agent of malaria, and find that unlike any other it adopts an open conformation.

In (post-)modern, plural societies, consisting of numerous subgroups, mutual respect between groups plays a central role for a constructive social and political life. In this article, we examine whether group members’ perception of being respected by outgroups fosters respect for these outgroups. In Study 1, we employed a panel sample of supporters of the Tea Party movement in the United States (N = 422). In Study 2, we employed a panel sample of members of the LGBTI community in Germany (N = 262). As disapproved target outgroups, we chose in Study 1 homosexuals in the United States, while in Study 2, we chose supporters of the German populist, right-wing political party „Alternative für Deutschland“. Our studies thus constituted a complementary, nearly symmetrical constellation of a liberal group and a conservative political group each. Among Tea Party movement supporters, respect from a disapproved outgroup consistently predicted respect for that outgroup. Among German LGBTI community members, this effect of respect from a disapproved outgroup was found in some of our analyses. For this latter sample, there was furthermore a tendency of societal respect to predict respect for a disapproved outgroup longitudinally. Additionally, we observed for both of our samples that respect from other ingroup members decreased respect for a disapproved outgroup. The dynamics of mutual respect in these two complementary intergroup contexts are discussed as well as the importance of direct intergroup reciprocity and superordinate group membership as routes to mutual respect.

In this article, we examine the significance of a superordinate identity of citizens in plural democratic societies with a focus on the combinations of the identification with a particular societal subgroup and the (dis-)identification with society as the superordinate group. We develop these combinations into the conceptions of embedded identity and dis-embedded identity. Embedded identity derives from the acknowledgment that one´s particular ingroup membership at a given level of ingroup-outgroup categorization is embedded in a higher-level group membership. In contrast, dis-embedded identity derives from the accentuation and prioritization of one’s particular ingroup membership at the expense of one’s membership in the superordinate group. Articulating Turner´s self-categorization theory with theoretical reasoning about normative frameworks, we hypothesized that embedded identity diminishes sympathy for non-normative ends and means, whereas dis-embedded identity fosters sympathy for non-normative ends and means. Two experiments, conducted with young people in Germany as research participants, supported these hypotheses: Embedded identity was unrelated or even negatively related to sympathy for non-normative ends and means, whereas dis-embedded identity was positively related to sympathy for non-normative ends and means. We highlight the contribution of our present research and that of social psychological research, more generally, to the understanding of (de)radicalization processes in plural democratic societies.

hnRNP A1 is an auxiliary factor that promotes the Microprocessor-mediated processing of pri-mir-18a, of the oncomiR-1 cluster. Here the authors employ an integrative structural biology approach and provide insights into the molecular mechanism of how hnRNP A1 facilitates pri-mir-18a biogenesis.

The article reports two experiments that examined politicization in the name of the majority population and intergroup polarization as a function of perceived grievances of the majority population. To manipulate perceived majority grievances, we used three different injustice frames (cultural, economic, political), each of which targeted an important arena of societal participation and thus a typical breeding ground for societal injustices and psychological grievances. In addition, both experiments included a (no frame) control condition. The samples recruited for the two experiments differed from each other in (left–right) political orientation and consequently in their perceptions of and reactions to potential majority grievances. The most striking differential influences were observed for the cultural grievance symbolized by the political correctness norm. However, both experiments provided evidence that majority politicization mediates the effect of majority grievances on intergroup polarization and that, in contrast to the divisive role of majority politicization, majority solidarity likely fosters social inclusion.

Many chromatin modifying proteins, including BRDT, contain bromodomains, which are known to interact with nucleosomes. Here, the authors find that BRDT interacts with nucleosomes via only one of its two bromodomains, and that the interaction involves contacts with DNA as well as acetylated histones.

Past research indicates that in political debates the same arguments are judged very differently depending on the perceiver's own position on the issue, because positions on controversial issues are often tied to collective identities. In this article, we test the assumption that equality-based respect from an opposing opinion-based group can reduce such biases. Results confirmed that identification as an opponent or proponent of a contested issue was negatively related to evaluations of outgroup arguments (Study 1) and that this negative link was no longer significant when intergroup respect was experimentally induced (Study 2). Results support the notion that disagreements over political issues are intergroup conflicts, in which different socio-political groups struggle for recognition, and that approaches that protect collective identities and improve intergroup relations should be employed to de-escalate them.

The succession of molecular events leading to eukaryotic translation reinitiation-whereby ribosomes terminate translation of a short open reading frame (ORF), resume scanning, and then translate a second ORF on the same mRNA-is not well understood. Density-regulated reinitiation and release factor (DENR) and multiple copies in T-cell lymphoma-1 (MCTS1) are implicated in promoting translation reinitiation both in vitro in translation extracts and in vivo. We present here the crystal structure of MCTS1 bound to a fragment of DENR. Based on this structure, we identify and experimentally validate that DENR residues Glu42, Tyr43, and Tyr46 are important for MCTS1 binding and that MCTS1 residue Phe104 is important for tRNA binding. Mutation of these residues reveals that DENR-MCTS1 dimerization and tRNA binding are both necessary for DENR and MCTS1 to promote translation reinitiation in human cells. These findings thereby link individual residues of DENR and MCTS1 to specific molecular functions of the complex. Since DENR-MCTS1 can bind tRNA in the absence of the ribosome, this suggests the DENR-MCTS1 complex could recruit tRNA to the ribosome during reinitiation analogously to the eukaryotic initiation factor 2 (eIF2) complex in cap-dependent translation.

Physiological function and pathology of the Alzheimer’s disease causing amyloid precursor protein (APP) are correlated with its cytosolic adaptor Fe65 encompassing a WW and two phosphotyrosine-binding domains (PTBs). The C-terminal Fe65-PTB2 binds a large portion of the APP intracellular domain (AICD) including the GYENPTY internalization sequence fingerprint. AICD binding to Fe65-PTB2 opens an intra-molecular interaction causing a structural change and altering Fe65 activity. Here we show that in the absence of the AICD, Fe65-PTB2 forms a homodimer in solution and determine its crystal structure at 2.6 Å resolution. Dimerization involves the unwinding of a C-terminal α-helix that mimics binding of the AICD internalization sequence, thus shielding the hydrophobic binding pocket. Specific dimer formation is validated by nuclear magnetic resonance (NMR) techniques and cell-based analyses reveal that Fe65-PTB2 together with the WW domain are necessary and sufficient for dimerization. Together, our data demonstrate that Fe65 dimerizes via its APP interaction site, suggesting that besides intra- also intermolecular interactions between Fe65 molecules contribute to homeostatic regulation of APP mediated signaling.

Missense single-nucleotide polymorphisms (mSNPs) in titin are emerging as a main causative factor of heart failure. However, distinguishing between benign and disease-causing mSNPs is a substantial challenge. Here, we research the question of whether a single mSNP in a generic domain of titin can affect heart function as a whole and, if so, how. For this, we studied the mSNP T2850I, seemingly linked to arrhythmogenic right ventricular cardiomyopathy (ARVC). We used structural biology, computational simulations and transgenic muscle in vivo methods to track the effect of the mutation from the molecular to the organismal level. The data show that the T2850I exchange is compatible with the domain three-dimensional fold, but that it strongly destabilizes it. Further, it induces a change in the conformational dynamics of the titin chain that alters its reactivity, causing the formation of aberrant interactions in the sarcomere. Echocardiography of knock-in mice indicated a mild diastolic dysfunction arising from increased myocardial stiffness. In conclusion, our data provide evidence that single mSNPs in titin's I-band can alter overall muscle behaviour. Our suggested mechanisms of disease are the development of non-native sarcomeric interactions and titin instability leading to a reduced I-band compliance. However, understanding the T2850I-induced ARVC pathology mechanistically remains a complex problem and will require a deeper understanding of the sarcomeric context of the titin region affected.

Abstract: Selecting appropriate learning services for a learner from the large number of heterogeneous knowledge sources is a complex and challenging task. This paper presents the idea of Smart Spaces for Learning. A Smart Space for Learning is defined as a distributed system (ie "space") that provides management support for the "smart" retrieval and consumption of heterogeneous learning services via Personal Learning Assistants. Personalisation and system interoperability play an important role for the realisation of a Smart Space for Learning. In this paper we illustrate and discuss how Semantic Web technologies such as RDF, TRIPLE, QEL and ontologies can be applied to create a Smart Space for Learning.Invited Commentary: McGreal, R. (2004) Commentary on: Simon, B., Dolog., P., Miklós, Z., Olmedilla, D. and Sintek, M. (2004). Conceptualising Smart Spaces for Learning. [PDF]Editors: Terry Anderson and Denise Whitelock.