Biochemistry

eLife Assessment

This manuscript provides important structural insights into the recognition and degradation of the host tRNA methyltransferase TRMT1 by SARS-CoV-2 protease nsp5 (Mpro). The data provide compelling support for the main conclusions of the authors. These results will be of interest to researchers studying structures, substrate recognition and specificity of viral proteases and their action on cellular targets.

eLife Assessment

This valuable study clarifies the mechanism by which the kinesin-10 motor protein, chromosome-associated kinesin, Kid (KIF22), enables chromosome movement during mitosis, demonstrating that human and Xenopus Kid proteins function as processive, homodimeric kinesins capable of processive microtubule plus-end motility. The convincing work highlights that Kid can recruit and transport duplex DNA along microtubules via its conserved C-terminal DNA binding domain, revising our understanding of chromokinesins' role in chromosome motility during mitosis. Although the data are robust, the manuscript would benefit from some editing for clarity.

eLife Assessment

The study describes a valuable new technology in the field of targeted protein degradation that allows identification of E3-ubiquitin ligases that target a protein of interest. The presented data are convincing, however, additional work will be needed to optimize for high-throughput evaluation. This technology will therefore serve the community in the initial stages of developing targeted protein degraders.

eLife Assessment

This important study presents interesting results aimed at explaining the effects of a human mutation on the mitochondrial import protein TIMM50 on mitochondrial function and neuronal excitability. While the evidence supporting the conclusions is convincing, the mechanisms driving changes in the levels of certain proteins within and outside the mitochondria (such as certain ion channels) remain unexplained. This paper will be of interest to scientists in the mitochondria field.

eLife Assessment

The manuscript reports on an important comparison of a range of approved clinical inhibitors for BTK used for the treatment of chronic lymphocytic leukemia (CLL). The authors provide compelling evidence for their claims, using a combination of HDX-MS and NMR spectroscopy. The novelty is that this study also seeks to evaluate resistance mutation bias. The manuscript will be of high interest to scientists working on protein drug interactions.

eLife Assessment

This fundamental study addresses the regulation of the MICAL-family of actin regulators by Rab GTPases, which play a key role in directing membrane trafficking within cells. The compelling evidence explains how Rab8 family members bind at two sites to allosterically regulate MICAL1, and relieve an auto-inhibited state unable to bind actin. This study lays the basis for further progress in understanding membrane trafficking and cytoskeleton dynamics in eukaryotic cells.

eLife Assessment

This study represents an important advance in our understanding of how certain inhibitors affect the behavior of voltage gated potassium channels. Robust molecular dynamics simulation and analysis methods lead to a new proposed inhibition mechanism with strength of support being mostly convincing, and incomplete in some aspects. This study has considerable significance for the fields of ion channel physiology and pharmacology and could aid in development of selective inhibitors for protein targets.

eLife Assessment

This study reveals that the malaria parasite protein PfHO, although lacking typical heme oxygenase activity, is essential for the survival of Plasmodium falciparum. Structural and localization analyses demonstrated that PfHO plays a critical role in maintaining the apicoplast, specifically in gene expression and biogenesis, suggesting an adaptive function for this protein in parasite biology. While the findings convincingly support the authors' claims, further investigation into apicoplast gene expression and the specific function of PfHO remains a future challenge. The topic and results are important and will be of interest to researchers studying various aspects of malaria, Plasmodium physiology, host-pathogen interactions, and heme metabolism.

eLife Assessment

The study provides a valuable showcase of a workflow to perform large-scale characterization of drug mechanisms of action using proteomics in which on-target and off-targets of 166 compounds using proteome solubility analysis in living cells and cell lysates were determined. The evidence supporting the claims of the authors is solid, however, the inclusion of more replicate experiments and more statistical rigor would have strengthened the study. This will be of broad interest to medicinal chemists, toxicologists, computational biologists and biochemists.

eLife Assessment

This manuscript describes an important study of a new lipid-mediated regulation mechanism of adenylyl cyclases. The biochemical evidence provided is convincing and will trigger more research in this mechanism. This manuscript will be of interest to all scientists working on lipid regulation and adenylyl cyclases.