Biochemistry and Chemical Biology

eLife assessment

This valuable study provides molecular-level insights into the functional mechanism of bacterial ice-nucleating proteins, detailing electrostatic interactions in the domain architecture of multimeric assemblies. The evidence supporting the claims of the authors is solid, with results from protein engineering experiments, functional assays, and cryo-electron tomography, while the proposed structural model of protein self-assembly remains hypothetical. The work is of broad interest to researchers in the fields of protein structural biology, biochemistry, and biophysics, with implications in microbial ecology and atmospheric glaciation.

eLife assessment

This study provides important insights into the structural biology and molecular mechanism of the sensory proteins ToxR/S that are associated with survival and virulence of the cholera pathogen. The structural studies are solid and supported by a series of biophysical experiments revealing a split, periplasmic protein binding interface for bile acid. The results are of interest to both protein biochemistry and pharmacology, potentially opening new routes for intervention in cholera disease.

eLife assessment

This fundamental study provides compelling evidence to explain how chemical variations within a set of kinase inhibitors drive the selection of specific Erk2 conformations. Conformational selection plays a critical role in targeting medically relevant kinases such as Erk2 and the findings reported here open new avenues for designing small molecule inhibitors that block the active site while also steering the population of the enzyme into active or inactive conformations. Since protein dynamics and conformational ensembles are essential for enzyme function, this work will be of broad interest to those working in drug development, signal transduction, and enzymology.

eLife assessment

This is an important biophysical study combining native mass spectrometry with mutant cycles to estimate the thermodynamic components of lipid A binding to the ABC transporter MsbA. Solid evidence supports the binding energies for lipid-protein interactions to MsbA using this approach, which could be later applied to other membrane proteins in general.

eLife assessment

This important study reports the identification of a new amino acid sequence motif (i.e., "internal beta-signal") on outer membrane proteins, which is recognized by beta-assembly machinery in gram-negative bacteria. The authors carried out rigorous experiments, providing compelling evidence in support of their conclusions. This work significantly advances our understanding of the biogenesis of outer membrane proteins.

eLife assessment

In this manuscript, the authors tested the hypothesis that Aβ42 toxicity arises from its proven affinity for γ-secretases. The authors provide useful findings, however, the results are incomplete and do not fit physiological conditions in the brain. The data will be of interest to all scientists working on neurodegenerative diseases.

eLife assessment

This fundamental study provides compelling evidence for a new mechanism of host-microbe interaction, with indole, produced by proliferating bacteria in the C. elegans digestive system, signalling through the host via the transcription factor DAF-16 to induce the expression of genes controlling bacterial growth in the gut. The work is relevant to a wide audience as it invites deeper research into this mechanism, while also serving as a template for similar microbiome/host interactions in other systems.

eLife assessment

This important study reports biochemical and structural experiments that were carried out to determine the molecular basis of calcium-sensitive regulation of the guanine exchange factor Ric8A by the neuronal calcium sensor 1 (NCS-1). Structural and biochemical evidence for the NCS-1/Ric8A interface is convincing, but evidence for the full-length interactions is incomplete due to the low resolution of cryo-EM maps. This work will have important implications for scientists interested in G-protein signaling and molecular interactions that contribute to synapse function.

eLife assessment

Dolgova et al present a well-written and important manuscript focused on the mechanism of MEMO1 function in tumor cells. The authors explore whether the mechanism of MEMO1 overexpression in breast cancer, especially TNBC, is related to regulating iron given evidence that MEMO1 binds multiple proteins in the iron regulation pathway. While the data is in part compelling, the claims are based on indirect evidence for a central role of MEMO1 in tumorogenesis and perhaps metastasis via its effect on iron homeostasis.

eLife assessment

This important study reports jAspSnFR3, a biosensor that enables high spatiotemporal resolution of aspartate levels in living cells. To develop this sensor, the authors used a structurally guided amino acid substitution in a glutamate/aspartate periplasmic binding protein to switch its specificity towards aspartate. The in vitro and in cellulo functional characterization of the biosensor is convincing, but evidence of the sensor's effectiveness in detecting small perturbations of aspartate levels and information on its behavior in response to acute aspartate elevations in the cytosol are still lacking.

eLife assessment

The manuscript by Paine and coworkers provides a fundamental improvement on how the enzymatic activity of CALPAIN7 (a Cys protease) influences cytokinesis mediated by the ESCRT (endosomal sorting complexes required for transport) pathway. The authors provide a convincing molecular and cellular basis for one of the several key steps involved in membrane fission during the separation of dividing eukaryotic cells. These findings should be of interest to a wide scientific audience including biochemists, structural biologists, and cell biologists.

eLife assessment

The manuscript by Salloum and colleagues shows that cholesterol-lowering statins can reduce mitochondrial cholesterol and impact epigenetic programs in macrophages. The findings could be valuable for understanding statin-mediated anti-inflammatory functions in macrophages. The major claims describing new mechanisms by which statins may regulate macrophage function via epigenetic programming are partially supported by the data presented.

eLife assessment

The authors attempted to show that syntaxin 6 (Stx6) delays PrP fibril formation and in presence of Stx6, PrP forms amorphous aggregates which are more toxic to neuronal cells, indicative of Stx6's anti-chaperone activity. This useful study has potential to provide important understanding of the molecular mechanism of PrP aggregation and neurotoxicity. However, the evidence supporting the physiological relevance and robustness of the assays is incomplete.

eLife assessment

This structural and biochemical study of the mouse homolog of acidic mammalian chitinase (AMCase) enhances our understanding of the pH-dependent activity and catalytic properties of mouse AMCase and sheds light on its adaptation to different physiological pH environments. The methods and analysis of data are solid, providing several lines of evidence to support a development of mechanistic hypotheses. While the findings and interpretation will be valuable to those studying AMCase in mice, the broader significance, including extension of the results to other species including human, remain unclear.

eLife assessment

The authors make the case that the assembly of MreB from Geobacillus, a Gram-positive organism differs substantially from MreB from the Gram-negative model organism, Escherichia coli. Although the conclusion of this valuable study would represent a major advance if correct, the evidence is currently incomplete, and significant additional work is necessary to ensure both rigor and impact.

eLife assessment

This valuable study advances our understanding of the evolution of protein complexes and their functions. Through convincing experimental and computational methodologies, the authors show that the specialization of protein function following gene duplication can be reversible. The work will be of interest to investigators working in biochemical evolution and those working on heat shock proteins.

eLife assessment

This study advances our understanding of the allosteric regulation of anaerobic ribonucleotide reductases (RNRs) by nucleotides, providing valuable new structural insight into class III RNRs containing ATP cones. The cryo-EM structural characterization of the system is solid, but some open questions remain about the interpretation of activity/binding assays and the newly incorporated HDX-MS results. The work will be of interest to biochemists and structural biologists working on ribonucleotide reductases and other allosterically regulated enzymes.

eLife assessment

This is a valuable analysis of the structure of Roseiflexus castenholzii native and carotenoid-depleted light harvesting complexes. The authors have investigated the relationship between Carotenoid pigment depletion in the photosynthesis-related light harvesting complex, the assembly of the prokaryotic reaction center LH complex, and quinone exchange in Roseiflexus castenholzii, a chlorosome-less filamentous anoxygenic phototroph that forms the deepest branch of photosynthetic bacteria. The evidence supporting the claims is solid, with application of rigorous biochemical and biophysical techniques, including cryo-electron microscopy of the purified of the RC-LH complexes with or depleted of carotenoids. This study will be of interest to biologists working on the evolution and diversity of prokaryotic photosynthetic apparatus.

eLife assessment

This important study combines engineered mesenchymal stem cells together with mouse models of kidney injury to determine the ability of these cells to reduce kidney damage upon acute kidney injury. The evidence supporting the claims is solid, although the inclusion of more than one type of stem cell and the use of male mice which are more prone to acute kidney injury, would strengthen the study. This work will be of interest to both basic scientists and clinicians working on mechanisms of kidney injury and repair.

eLife assessment

This important study presents convincing evidence on how the sea slug Aplysia kurodai optimizes its digestion of brown algae, in a classical predator-prey 'arms race' at the molecular level. The experimental protein structures and enzyme assays provide support for the claims of how A. kurodai avoids inhibition by algal compounds, and also hold promise for biotechnological applications.