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  1. Deep Mutagenesis of a Transporter for Uptake of a Non-Native Substrate Identifies Conformationally Dynamic Regions

    This article has 9 authors:
    1. Heather J Ellis
    2. Matthew Chan
    3. Balaji Selvam
    4. Evan Walter
    5. Christine A Devlin
    6. Steven K Szymanski
    7. Loren Keith Henry
    8. Diwakar Shukla
    9. Erik Procko
    This article has been curated by 1 group:
    • Curated by eLife

      eLife assessment

      Serotonin is an important neurotransmitter and its synaptic concentration is controlled by re-uptake by the sodium-coupled serotonin transporter SERT. The manuscript by Chan et al reports results from a systematic deep mutagenesis approach to study the surface expression and APP+ (5HT analogue) transport mechanism of the human serotonin transporter. The authors complement this experimental evidence with large-scale molecular simulations of the transporter in the presence of APP+. The use of deep mutagenesis and large-scale adaptive sampling simulations is impressive, and could contribute to understanding the structural requirements for folding and how transporters evolve to recognize different substrates.

    Reviewed by eLife

    This article has 5 evaluationsAppears in 2 listsLatest version Latest activity
  2. SIRT2-Mediated ACSS2 K271 Deacetylation Suppresses Lipogenesis Under Nutrient Stress

    This article has 3 authors:
    1. Rezwana Karim
    2. Wendi Teng
    3. Hening Lin
    This article has been curated by 1 group:
    • Curated by eLife

      eLife assessment

      This useful study describes a role for acetylation in controlling the stability of acetyl-CoA synthetase 2, which converts acetate to acetyl-CoA for de novo lipid synthesis. While some aspects of the study are solid, the overall evidence supporting these findings is incomplete. Including additional critical controls for protein levels and stability and extending the findings to additional cell lines will strengthen the study. This work will be of interest to researchers studying lipid metabolism and related diseases.

    Reviewed by eLife

    This article has 4 evaluationsAppears in 2 listsLatest version Latest activity
  3. The co-receptor Tspan12 directly captures Norrin to promote ligand-specific β-catenin signaling

    This article has 3 authors:
    1. Elise S. Bruguera
    2. Jacob P. Mahoney
    3. William I. Weis
    This article has been curated by 1 group:
    • Curated by eLife

      eLife assessment

      This is a fundamental study that addresses the key question of how the tetraspanin Tspan12 functions biochemically as a co-receptor for Norrin to initiate β-catenin signaling. The strength of the work lies in the rigorous and compelling binding analyses involving various purified receptors, co-receptors, and ligands, as well as molecular modeling by AlphaFold that was subsequently validated by an extensive series of mutagenesis experiments. The study advances the field by providing a novel mechanism of co-receptor function and shedding new light on how signaling specificity is achieved in the complex Wnt/Norrin signaling system.

    Reviewed by eLife

    This article has 4 evaluationsAppears in 2 listsLatest version Latest activity
  4. Structural analysis of the dynamic ribosome-translocon complex

    This article has 4 authors:
    1. Aaron J. O. Lewis
    2. Frank Zhong
    3. Robert J. Keenan
    4. Ramanujan S. Hegde
    This article has been curated by 1 group:
    • Curated by eLife

      eLife assessment

      This landmark work by Lewis and Hegde represents the most significant breakthrough in membrane and secretory biogenesis in recent years. Their work reveals with outstanding clarity how nascent transmembrane segments can pass through the gate of Sec61 into the ER membrane through the coordinated motions of a conformationally and compositionally dynamic machine. Among many other insights, the authors discovered how a new factor, RAMP4, contributes to the formation and function of the lateral gate for certain substrates. The technical quality of the work is exceptional, setting the bar appropriately high.

    Reviewed by eLife

    This article has 8 evaluationsAppears in 2 listsLatest version Latest activity
  5. Large-scale characterization of drug mechanism of action using proteome-wide thermal shift assays

    This article has 6 authors:
    1. Jonathan G. Van Vranken
    2. Jiaming Li
    3. Julian Mintseris
    4. Meagan Gadzuk-Shea
    5. Steven P. Gygi
    6. Devin K. Schweppe
    This article has been curated by 1 group:
    • Curated by eLife

      eLife assessment

      This study is a useful showcase of a workflow to perform large-scale characterization of drug mechanisms of action using proteomics. The work is backed by solid evidence, however, more statistical analyses and a user-friendly interface to enhance data mining by the readers are recommended. The strengths of this study include the large number of compounds tested within a common workflow and well-described experimental protocols. This will be of broad interest to medicinal chemists, toxicologists, and biochemists.

    Reviewed by eLife

    This article has 4 evaluationsAppears in 2 listsLatest version Latest activity
  6. Impact of the clinically approved BTK inhibitors on the conformation of full-length BTK and analysis of the development of BTK resistance mutations in chronic lymphocytic leukemia

    This article has 8 authors:
    1. Raji E. Joseph
    2. Thomas E. Wales
    3. Sandrine Jayne
    4. Robert G. Britton
    5. D. Bruce Fulton
    6. John R. Engen
    7. Martin J. S. Dyer
    8. Amy H. Andreotti
    This article has been curated by 1 group:
    • Curated by eLife

      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 solid 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 scope of the study is highly exciting but would benefit from a clear link of the biophysical studies to the functional assays - specifically nucleotide binding.

    Reviewed by eLife

    This article has 3 evaluationsAppears in 2 listsLatest version Latest activity
  7. Ligand Response of Guanidine-IV riboswitch at Single-molecule Level

    This article has 3 authors:
    1. Lingzhi Gao
    2. Dian Chen
    3. Yu Liu
    This article has been curated by 1 group:
    • Curated by eLife

      eLife assessment

      This study presents valuable findings on the ligand- and ion-dependent structural dynamics of a transcriptional riboswitch. The single-molecule data presented are solid and prompts intriguing hypotheses and models, which will undoubtedly stimulate future structural analyses. These findings are of considerable interest to biochemists and biophysicists engaged in the study of RNA structure and riboswitch mechanisms.

    Reviewed by eLife

    This article has 9 evaluationsAppears in 2 listsLatest version Latest activity
  8. Crosslinking by ZapD drives the assembly of short FtsZ filaments into toroidal structures in solution

    This article has 12 authors:
    1. Adrián Merino-Salomón
    2. Jonathan Schneider
    3. Leon Babl
    4. Jan-Hagen Krohn
    5. Marta Sobrinos-Sanguino
    6. Tillman Schäfer
    7. Juan R. Luque-Ortega
    8. Carlos Alfonso
    9. Mercedes Jiménez
    10. Marion Jasnin
    11. Petra Schwille
    12. Germán Rivas
    This article has been curated by 1 group:
    • Curated by eLife

      eLife assessment

      The formation of the Z-ring at the time of bacterial cell division interests researchers working towards understanding cell division across all domains of life. The manuscript by Jasnin et al reports the cryoET structure of toroid assembly formation of FtsZ filaments driven by ZapD as the cross linker. The findings are important and have the potential to open a new dimension in the field, but the evidence to support these exciting claims is currently inadequate.

    Reviewed by eLife

    This article has 5 evaluationsAppears in 2 listsLatest version Latest activity
  9. Bacterial exonuclease III expands its enzymatic activities on single-stranded DNA

    This article has 11 authors:
    1. Hao Wang
    2. Chen Ye
    3. Qi Lu
    4. Zhijie Jiang
    5. Chao Jiang
    6. Chun Zhou
    7. Na Li
    8. Caiqiao Zhang
    9. Guoping Zhao
    10. Min Yue
    11. Yan Li
    This article has been curated by 1 group:
    • Curated by eLife

      eLife assessment

      This manuscript highlights single-stranded DNA exo- and endo-nuclease activities of ExoIII as a potential caveat and an underestimated source of decreased efficiency in its use in biosensor assays. The data present solid evidence for the ssDNA nuclease activity of ExoIII and identifies residues that contribute to it. The findings are useful, but some aspects in the study remain incomplete.

    Reviewed by eLife

    This article has 8 evaluationsAppears in 2 listsLatest version Latest activity
  10. SUMO’s intrinsically disordered N-terminus is an intramolecular inhibitor of SUMO - SIM interactions

    This article has 11 authors:
    1. Sebastian M. Richter
    2. Fan Jin
    3. Tobias Ritterhoff
    4. Aleksandra Fergin
    5. Eric Maurer
    6. Andrea Frank
    7. Alex Hajnal
    8. Rachel Klevit
    9. Frauke Gräter
    10. Annette Flotho
    11. Frauke Melchior
    This article has been curated by 1 group:
    • Curated by eLife

      eLife assessment

      This work demonstrates an important regulatory role of the N-terminal disordered tail of small ubiquitin-like modifier (SUMO) proteins, which modulates the function of a variety of proteins in eukaryotic cells. The authors present convincing evidence that the N-terminal region of SUMO inhibits its own interaction with downstream effector proteins and SUMOylation targets. This new discovery significantly advances the field by providing a possible explanation of how SUMO paralogues select their effectors and SUMOylation targets.

    Reviewed by eLife

    This article has 3 evaluationsAppears in 2 listsLatest version Latest activity
  11. Balanced Interplay Between Hsp110, Hsp70 and Class B J-Domain Protein Improves Aggregate Disassembly

    This article has 6 authors:
    1. Wiktoria Sztangierska
    2. Hubert Wyszkowski
    3. Maria Pokornowska
    4. Michał Rychłowski
    5. Krzysztof Liberek
    6. Agnieszka Kłosowska
    This article has been curated by 1 group:
    • Curated by eLife

      eLife assessment

      This study provides an important insight into the mechanisms of cooperation between Hsp70 and its cochaperones during protein disaggregation. Based on compelling evidence, the authors demonstrate that Hsp110 increases Hsp70 recruitment to protein aggregates. This work is of broad interest to biochemists and cell biologists working in the protein homeostasis field.

    Reviewed by eLife

    This article has 4 evaluationsAppears in 2 listsLatest version Latest activity
  12. Senescent cells inhibit muscle differentiation via the SASP-lipid 15d-PGJ 2 mediated modification and control of HRas

    This article has 7 authors:
    1. Swarang Sachin Pundlik
    2. Alok Barik
    3. Ashwin Venkateshvaran
    4. Snehasudha Subhadarshini Sahoo
    5. Mahapatra Anshuman Jaysingh
    6. Raviswamy G H Math
    7. Arvind Ramanathan
    This article has been curated by 1 group:
    • Curated by eLife

      eLife assessment

      This manuscript provides useful information about the lipid metabolite 15d-PGJ2 as a potential regulator of myoblast senescence. The authors provide experimental evidence that 15d-PGJ2 inhibits myoblast proliferation and differentiation by binding and regulating HRas. However, the manuscript is incomplete in its current form, as it lacks robust support from the data regarding the main conclusions related to senescence and technical concerns related to the senescence models used in this study.

    Reviewed by eLife

    This article has 4 evaluationsAppears in 2 listsLatest version Latest activity
  13. Activation of Polycystin-1 Signaling by Binding of Stalk-derived Peptide Agonists

    This article has 6 authors:
    1. Shristi Pawnikar
    2. Brenda S. Magenheimer
    3. Ericka Nevarez Munoz
    4. Allan Haldane
    5. Robin L. Maser
    6. Yinglong Miao
    This article has been curated by 1 group:
    • Curated by eLife

      eLife assessment

      This joint computational/experimental study demonstrates the ability of synthetic peptides derived from the stalk-tethered agonist in Polycystin-1 (PC1) to re-activate signaling by a stalkless C-terminal fragment of PC1. The study is valuable as it discovered peptide agonists for PC1 and the integrated in vitro and in silico approach is potentially applicable to the analysis of related systems. The line of evidence presented in the current manuscript is considered incomplete and additional experiments are needed as controls and for validating the simulations.

    Reviewed by eLife

    This article has 4 evaluationsAppears in 2 listsLatest version Latest activity
  14. The cryo-EM structure of ASK1 reveals an asymmetric architecture allosterically modulated by TRX1

    This article has 4 authors:
    1. Karolina Honzejkova
    2. Dalibor Kosek
    3. Veronika Obsilova
    4. Tomas Obsil
    This article has been curated by 1 group:
    • Curated by eLife

      eLife assessment

      This important manuscript reports the cryo-EM structure of the ASK1 protein, which is a critical regulator of the MAPKs, JNKs, and p38 MAPKs in diverse cellular stress responses. The evidence of ASK1 interaction with TRX1 is compelling and will eventually allow the discovery of small molecule inhibitors of ASK1 activity.

    Reviewed by eLife

    This article has 4 evaluationsAppears in 2 listsLatest version Latest activity
  15. Dual engagement of the nucleosomal acidic patches is essential for deposition of histone H2A.Z by SWR1C

    This article has 6 authors:
    1. Alexander S Baier
    2. Nathan Gioacchini
    3. Priit Eek
    4. Erik M Leith
    5. Song Tan
    6. Craig L Peterson
    This article has been curated by 1 group:
    • Curated by eLife

      eLife assessment

      This manuscript presents an important analysis of the role that the nucleosome acidic patch plays in SWR1-catalyzed histone exchange. This manuscript contains convincing data which significantly expands our understanding of the complex process of H2A.Z deposition by SWR1 and therefore would be of interest to a broad readership.

    Reviewed by eLife

    This article has 7 evaluationsAppears in 2 listsLatest version Latest activity
  16. Kinases in motion: impact of protein and small molecule interactions on kinase conformations

    This article has 14 authors:
    1. Valentina Kugler
    2. Selina Schwaighofer
    3. Andreas Feichtner
    4. Florian Enzler
    5. Jakob Fleischmann
    6. Sophie Strich
    7. Sarah Schwarz
    8. Rebecca Wilson
    9. Philipp Tschaikner
    10. Jakob Troppmair
    11. Veronika Sexl
    12. Pascal Meier
    13. Teresa Kaserer
    14. Eduard Stefan
    This article has been curated by 1 group:
    • Curated by eLife

      eLife assessment

      This article reports an important fluorescence-based reporter system to evaluate kinase conformations. This assay is applied to four different kinases that have very unique regulatory features, thereby indicating that the assay can be used to provide solid evidence on the conformational state of a large number of kinases. This paper will be of interest to researchers working on kinases and their conformational states.

    Reviewed by eLife

    This article has 3 evaluationsAppears in 2 listsLatest version Latest activity
  17. Paradoxical dominant negative activity of an immunodeficiency-associated activating PIK3R1 variant

    This article has 7 authors:
    1. Patsy R. Tomlinson
    2. Rachel Knox
    3. Olga Perisic
    4. Helen C. Su
    5. Gemma V. Brierley
    6. Roger L. Williams
    7. Robert K. Semple
    This article has been curated by 1 group:
    • Curated by eLife

      eLife assessment

      The authors identify new mechanisms that link a PIK3R1 mutant to cellular signaling and division in Activated PI3 Kinase Delta Syndrom 1 and 2 (APDS1/2). The conclusion that this mutant serves as a dominant negative form of the protein, impacting PI3K complex assembly and IRS/AKT signaling, is important, and the evidence from constitutive and inducible systems in cultured cells is convincing. Nevertheless, there are several limitations relating to differences between cell lines and expression systems, as well as more global characterization of the protein interaction landscape, which would further enhance the work.

    Reviewed by eLife

    This article has 3 evaluationsAppears in 2 listsLatest version Latest activity
  18. Uncovering the BIN1-SH3 interactome underpinning centronuclear myopathy

    This article has 10 authors:
    1. Boglarka Zambo
    2. Evelina Edelweiss
    3. Bastien Morlet
    4. Luc Negroni
    5. Mátyás Pajkos
    6. Zsuzsanna Dosztányi
    7. Soren Ostergaard
    8. Gilles Trave
    9. Jocelyn Laporte
    10. Gergo Gogl
    This article has been curated by 1 group:
    • Curated by eLife

      eLife assessment

      This work describes a novel affinity interactomics approach that allows investigators to identify networks of protein-protein interactions in cells. The important findings presented here describe the application of this technique to the SH3 domain of the membrane remodeling Bridging Integrator 1 (BIN1), the truncation of which leads to centronuclear myopathy. The authors present solid evidence that BIN1 SH3 engages with an unexpectedly high number of cellular proteins, many of which are linked to skeletal muscle disease, and evidence is presented to suggest that BIN1 may play a role in mitosis creating the potential for new avenues in drug development efforts. Some of the findings, however, remain rather preliminary, lack sufficient replicates and may require additional experiments to definitively support the conclusions.

    Reviewed by eLife

    This article has 7 evaluationsAppears in 2 listsLatest version Latest activity
  19. Human pannexin 1 channel is not phosphorylated by Src tyrosine kinase at Tyr199 and Tyr309

    This article has 5 authors:
    1. Zheng Ruan
    2. Junuk Lee
    3. Yangyang Li
    4. Juan Du
    5. Wei Lü
    This article has been curated by 1 group:
    • Curated by eLife

      eLife assessment

      The current manuscript re-examines an established claim in the literature that human PANX-1 is regulated by Src kinase phosphorylation at two tyrosine residues, Y199 and Y309. This issue is important for our understanding of Pannexin channel regulation. The authors present an extensive series of experiments that fail to detect PANX-1 phosphorylation at these sites. Although the authors' approach is more rigorous than the previous studies, this work relies primarily on negative results that are not unambiguously definitive; the work nonetheless provides a compelling reason for the field to reexamine conclusions drawn in earlier studies.

    Reviewed by eLife

    This article has 9 evaluationsAppears in 3 listsLatest version Latest activity
  20. Daptomycin forms a stable complex with phosphatidylglycerol for selective uptake to bacterial membrane

    This article has 6 authors:
    1. Pragyansree Machhua
    2. Vignesh Gopalakrishnan Unnithan
    3. Yu Liu
    4. Yiping Jiang
    5. Lingfeng Zhang
    6. Zhihong Guo
    This article has been curated by 1 group:
    • Curated by eLife

      eLife assessment

      This valuable study describes the molecular mechanism of daptomycin insertion into bacterial membranes. The authors provide solid in vitro evidence for the early events of daptomycin interaction with phospholipid headgroups and stronger, specific interaction with phosphatidylglycerol. This work will be of interest to bacterial membrane biologists and biochemists working in the antimicrobial resistance field.

    Reviewed by eLife

    This article has 4 evaluationsAppears in 2 listsLatest version Latest activity