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Rearrangement of the B cell receptor is sequential, and pairing of the successfully assembled heavy chain with the surrogate light chain proteins VpreB and λ5 to form the pre-B cell receptor is an important checkpoint signal for continued B cell development. Here, the authors show that λ5 plays a key role in the multi-step assembly process involving association-induced folding reactions.

Neutral homoaromatic hydrocarbons—which possess an interrupted π-system yet display aromatic properties owing to through-space or through-bond interactions—have remained rare as they are typically unstable. Now a class of stable neutral homoaromatic homoannulenes has been synthesized, including one that acts as a photoswitch through a reversible [1, 11] sigmatropic rearrangement.

Demonstration of high performance, upscaling and integration of ultra-lightweight perovskite solar cells are still rare. Hailegnaw et al. develop 2D perovskite solar cells based on methylbenzyl ammonium iodide with improved specific power and stability, showing scalability and integration in drones.

ETS transcription factor ERG has been implicated in numerous cancers, including leukemia. Here, the authors show that ERG interaction with the NCoR-HDAC3 co-repressor complex is essential for its leukemogenic activity. Highlighting this interaction as a potential therapeutic target, HDAC3 inhibition led to reduced growth of ERG-dependent leukemia cells in vitro and in vivo.

Hsp90 is a molecular chaperone important for protein homeostasis. Here, the authors show that the conformational transitions during the Hsp90 ATPase cycle are conserved from yeast to humans, but a few mutations alter cycle timing and dynamics.

Small heat shock proteins (sHsps) form large spherical assemblies and their regulation is not well understood. Here, the authors provide insights into the mechanism of Hsp26 activation by characterising phospho-mimetic mutants of yeast Hsp26. They present cryo-EM structures of the wild-type Hsp26 40mer and its phospho-mimetic mutants that reveal the location of the thermosensor in the oligomer, and the authors also show that the thermosensor domain is targeted by phosphorylation, which relieves the intrinsic inhibition of chaperone activity.

AL amyloidosis is caused by the accumulation of overproduced light chain (LC) fragments as fibrils in patient organs and it is the most prevalent systemic amyloidosis. Here, the authors combine biochemical and biophysical experiments to characterise the lag phase of a patient-derived truncated LC and they identify structural transitions that precede fibril formation.

Certain bovine antibodies have ultra-long long complementarity-determining regions (CDRs) that contain a knob for antigen interaction, which is connected to the antibody through a stalk. Here, the authors combine biophysical experiments and MD simulations and show that the stalk length is critical for the folding and stability of these antibodies. The authors also demonstrate that ultra-long bovine CDRs can be grafted into human antibodies, and furthermore show that de novo designed mini-domains that bind to the SARS-CoV-2 spike protein with high affinity can be integrated as a knob in ultra-long CDRs in bovine and human antibodies, which neutralize SARS-CoV-2.

p23 is a co-chaperone of Hsp90 but its mode of action is mechanistically not well understood. Here, the authors combine in vitro and yeast in vivo assays, biochemical measurements and NMR experiments to characterize p23 and identify two conserved helical elements in the intrinsically disordered C-terminal tail of p23 that together with the folded domain of p23 regulate the Hsp90 ATPase activity and affect the binding and maturation of Hsp90 clients.

Biochemical and biophysical analyses of eye lenses from mouse strains that develop cataract due to mutations in α-, β-, or γ-crystallin proteins reveal that the mutant protein levels are largely reduced, but other crystallin proteins, including α-crystallins, precipitate.

Hypothalamic melanocortin neurons control energy homoeostasis by modulating appetite. Here, the authors reveal a role for the transcription factor Tbx3 as a regulator of the peptidergic identity and function of immature and mature mouse melanocortin neurons.

Methylation of a lysine residue in Hsp90 is a recently discovered post-translational modification but the mechanistic effects of this modification have remained unknown so far. Here the authors combine biochemical and biophysical approaches, molecular dynamics (MD) simulations and functional experiments with yeast and show that this lysine is a switch point, which specifically modulates conserved Hsp90 functions including co-chaperone regulation and client activation.

Future bioinspired locomotion systems need design’s agility and adaptiveness. Here, the authors report a musculoskeletal leg design which leverages multi-layered electrohydraulic actuators to achieve highly energy-efficient and versatile motion.

Oligomers of human αA-crystallin are characterized structurally via a hybrid approach, combining cryo-EM, cross-linking/mass spectrometry, NMR and modeling, providing insight into their dynamic behavior and heterogeneity and revealing that oxidized oligomers can also act as chaperones.

S. cerevisiae encodes two Hsp90 isoforms, the constitutively expressed Hsc82 and stress-inducible Hsp82 that are 97% identical. Here, the authors combine a range of biophysical methods and show that they differ in their enzymatic properties, resilience to stress and client range, which suggests that they evolved to provide fine-tuned chaperone assistance under physiological and stress conditions.

Hsp90 is a molecular chaperone with a wide array of client proteins, including the tumor suppressor p53. Now the structure and interaction of p53 DNA-binding domain with full-length Hsp90 or Hsp90 fragments have been studied by NMR and other biophysical methods. The results indicate that p53 interacts with multiple domains of Hsp90 and adopts a native-like state.

The chaperone Hsp90 interacts with different cochaperones during its reaction cycle. Now a ternary complex of Hsp90 with ATPase inhibitor Sti1 and prolyl isomerase Cpr6 is identified as an intermediate by fluorescence resonance energy transfer (FRET) and analytical ultracentrifugation, with support from genetic data.

The chaperones Hsp70 and Hsp90 are physically linked via the cochaperone Sti1/Hop, that has two binding sites for Hsp70. Here, Röhl et al.show that binding of Hsp90 changes the conformation of Sti1/Hop and determines to which site Hsp70 binds, perhaps facilitating transfer of client proteins from Hsp70 to Hsp90.

The role of co-chaperone and Hsp90 activator Aha1 is now examined in conjunction with other co-chaperones in vivo and in vitro, to reveal how they regulate the progression of the Hsp90 cycle. Aha1 and Cpr6 interact with and activate Hsp90 in a synergistic manner and displace the inhibitory co-chaperone Sti1. Aha1 is eventually released from Hsp90 by p23.

The Hsp90 chaperone is responsible for the stabilization of a large variety of regulatory proteins. By labeling the subunits in the Hsp90 homodimer with different dyes and in different positions, the kinetics of Hsp90 conformational changes along the ATPase cycle was characterized, revealing different intermediate states and the different roles of cochaperones.

Analyses of Hsp90 mutants show no correlation between the speed of ATP turnover and chaperone activity in vivo, indicating that timing of conformational transitions, rather than cycle speed, is essential for Hsp90 function.

BiP is an Hsp70 chaperone in the endoplasmic reticulum (ER) and is crucial for protein folding and quality control. Using single-molecule and ensemble FRET, the conformational cycle of BiP has now been defined. Movement of the lid domain of BiP allows this chaperone to discriminate between peptide and protein substrates.

The ER-resident Hsp70 BiP is regulated by NEF Bap. The interactions between BiP and Bap are now dissected using biochemistry, molecular modeling and smFRET approaches, revealing that Bap affects both domains of BiP, to coordinate release of substrate and nucleotide.

The heat shock protein 90 (Hsp90) chaperone undergoes large conformational changes during its functional cycle. Here the authors combine in vivo, biochemical, biophysical and computational approaches and provide insights into the allosteric regulation of Hsp90 by identifying and characterizing a switch point in the Hsp90 middle domain.

The heat shock protein 90 (HSP90) chaperone machinery is a key regulator of proteostasis. Recent progress has shed light on the interactions of HSP90 with its clients and co-chaperones, and on their functional implications. This opens up new avenues for the development of drugs that target HSP90, which could be valuable for the treatment of cancers and protein-misfolding diseases.

The chaperone Hsp90 uses the free energy from ATP hydrolysis to control the folding of client proteins in eukaryotic cells. Here the authors provide mechanistic insights into how its catalytic activity is coupled to conformational changes by combining large-scale molecular simulations with NMR, FRET and SAXS experiments.

Fusion of ACE2 to IgM-Fc results in hexameric ACE2-IgM-Fc proteins with potent virus neutralization efficiency of patient-isolated SARS-CoV and SARS-CoV-2 variants.

Hsp90 is a molecular chaperone essential for the maintenance of cellular homeostasis. Now multiple approaches are used to study the deleterious effects of mutations in β-strand 8 of the N domain of Hsp90 and the role of the charged linker between N and M domains in mediating such effects.

Hsp70 and Hsp90 cooperate to fold client proteins, aided by co-chaperones such as Hop. Here Alvira et al. determine EM structures of various combinations of Hsp70, Hsp90, Hop and a client protein to shed structural insight into the mechanism of client protein transfer from one chaperone to the other.

Solid-state and solution NMR spectroscopy provide insights into the chaperone αB-crystallin's highly dynamic assembly, which is instrumental in its distinct interactions with a wide range of structurally variable clients.

The Hsp90 chaperone is responsible for the stabilization of a large variety of regulatory proteins. Single-molecule FRET was used to examine the conformational dynamics of Hsp90 in its different nucleotide-bound states. The findings suggest that, in the absence of substrate and cochaperone proteins, Hsp90's conformational changes are not strongly coupled to ATP hydrolysis.

EasyFuse detects gene fusions in cancer transcriptomes for personalized immunotherapy.

Electrocatalytic hydrogenations of organics allow water to be used as the proton source but are limited by low substrate solubility in aqueous media or by low performance in organic electrolytes. Now, a Pickering emulsion system for electrocatalytic hydrogenation is presented to overcome those issues, where the hydrogenation reaction occurs at the interface between the aqueous and organic phases.

This Expert Recommendation provides a guide to setting up machine learning projects that are less time-consuming and more likely to lead to robust and useful scientific insights.

Impact models projections are used in integrated assessments of climate change. Here the authors test systematically across many important systems, how well such impact models capture the impacts of extreme climate conditions.

Nested sampling is an algorithm for computing Bayesian inference and high-dimensional integrals. This Primer introduces the nested sampling algorithm and variations, highlighting its use across various areas of physical science, from cosmology to particle physics.

An intrinsic antiferromagnetic topological insulator, MnBi₂Te₄, is theoretically predicted and then realized experimentally, with implications for the study of exotic quantum phenomena.

The solution structure, stability, and dynamics of a broadly-acting antiviral ACE2-IgG-Fc fusion protein are determined. Small chemical compounds binding to ACE2 can be used to drastically increase the thermal stability of the ACE2 domain.

Biophysical approaches reveal how a mutation in the constant light chain domain of a patient-derived antibody destabilizes the constant domain, prevents the dimerization of the light chain, and makes it more prone to proteolytic cleavage, unleashing the amyloidogenic potential of the isolated variable domain.