Biochemistry

Large-scale characterization of drug mechanism of action using proteome-wide thermal shift assays

1. Jonathan G Van Vranken
2. Jiaming Li
3. Julian Mintseris
4. Ting-Yu Wei
5. Catherine M Sniezek
6. Meagan Gadzuk-Shea
7. Steven P Gygi
8. Devin K Schweppe

• Curated by eLife

  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.

Reviewed by PREreview, eLife

The membrane domains of mammalian adenylyl cyclases are lipid receptors

1. Marius Landau
2. Sherif Elsabbagh
3. Harald Gross
4. Adrian CD Fuchs
5. Anita CF Schultz
6. Joachim E Schultz

• Curated by eLife

  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.

Reviewed by eLife, Arcadia Science

Unanticipated mechanisms of covalent inhibitor and synthetic ligand cobinding to PPARγ

1. Jinsai Shang
2. Douglas J Kojetin

• Curated by eLife

  eLife Assessment

  This landmark study elucidates the intricate structural mechanisms by which both covalent and non-covalent synthetic ligands can co-occupy the binding pocket of the nuclear receptor transcription factor PPARγ. Through a compelling integration of structural, biochemical, and biophysical evidence, the authors challenge the reliability of two commonly used covalent inhibitors. These findings have far-reaching implications for the broader field of nuclear receptor research. This work will be of high interest to structural biologists and biochemists exploring ligand interactions within the nuclear receptor superfamily.

Reviewed by eLife

Structural insights into human propionyl-CoA carboxylase (PCC) and 3-methylcrotonyl-CoA carboxylase (MCC)

1. Fayang Zhou
2. Yuanyuan Zhang
3. Yuyao Zhu
4. Qiang Zhou
5. Yigong Shi
6. Qi Hu

• Curated by eLife

  eLife Assessment

  This study presents the cryo-EM structures of two human biotin-dependent mitochondria carboxylases involved in various biological pathways, including the metabolism of certain amino acids, cholesterol, and odd chain fatty acids. The cryo-EM structures offer a valuable addition to the structural description of biotin-dependent carboxylases and provide solid evidence to support the major conclusions of this study. This paper would be of interest to biochemists and structural biologists working on biotin-dependent carboxylases.

Reviewed by eLife

The intrinsically disordered N-terminus of SUMO1 is an intramolecular inhibitor of SUMO1 interactions

1. Sebastian M Richter
2. Fan Jin
3. Tobias Ritterhoff
4. Aleksandra Fergin
5. Eric Maurer
6. Andrea Frank
7. Michael Daube
8. Alex Hajnal
9. Rachel Klevit
10. Frauke Gräter
11. Annette Flotho
12. Frauke Melchior

• 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 modulate the function of various proteins in eukaryotic cells. The authors present convincing evidence that the N-terminal tail of SUMO inhibits SUMO's interaction with downstream effector proteins and SUMOylation targets, and that this regulatory mechanism depends on the SUMO paralogue or the phosphorylation of the N-terminal tail. This discovery significantly advances the field by providing a possible explanation of how SUMO paralogues select their effectors and SUMOylation targets.

Reviewed by eLife

Bioorthogonal labeling of chitin in pathogenic Candida species reveals biochemical mechanisms of hyphal growth and homeostasis

1. Caroline Williams
2. Bella R. Carnahan
3. Stephen N. Hyland
4. Catherine L. Grimes

Reviewed by PREreview

Elucidating ATP’s role as solubilizer of biomolecular aggregate

1. Susmita Sarkar
2. Saurabh Gupta
3. Chiranjit Mahato
4. Dibyendu Das
5. Jagannath Mondal

• Curated by eLife

  eLife assessment

  The authors combined molecular dynamics simulations and experiments to study the role of ATP as a hydrotrope of protein aggregates. The topic is of major current interest and thus the study potentially makes an important contribution to the community. With the revised version, the level of evidence is considered generally solid, although there remains concern regarding the unusually high ATP concentration used in the simulation.

Reviewed by eLife

Dimer-monomer transition defines a hyper-thermostable peptidoglycan hydrolase mined from bacterial proteome by lysin-derived antimicrobial peptide-primed screening

1. Li Zhang
2. Fen Hu
3. Zirong Zhao
4. Xinfeng Li
5. Mingyue Zhong
6. Jiajun He
7. Fangfang Yao
8. Xiaomei Zhang
9. Yuxuan Mao
10. Hongping Wei
11. Jin He
12. Hang Yang

• Curated by eLife

  eLife assessment

  This valuable study explores a new strategy of lysin-derived antimicrobial peptide-primed screening to find peptidoglycan hydrolases from bacterial proteomes. Using this strategy, the authors identified five peptidoglycan hydrolases from Acinetobacter baumannii, which they tested on various Gram-positive and Gram-negative pathogens for antimicrobial activity. The revised manuscript addressed most of the prior concerns, and the data presented are solid and will be of interest to microbiologists.

Reviewed by eLife

Disordered proteins interact with the chemical environment to tune their protective function during drying

1. Shraddha KC
2. Kenny H Nguyen
3. Vincent Nicholson
4. Annie Walgren
5. Tony Trent
6. Edith Gollub
7. Paulette Sofia Romero-Perez
8. Alex S Holehouse
9. Shahar Sukenik
10. Thomas C Boothby

• Curated by eLife

  eLife assessment

  This important study investigates the sensitivity to endogenous cosolvents of three families of intrinsically disordered proteins involved with desiccation. The findings, drawn from well-designed experiments and calculations, suggest a functional synergy between sensitivity to small molecule solutes and convergent desiccation protection strategy. The evidence is found to be convincing, and the authors provide appropriate caveats since the study's conclusions are based on a small number of proteins. This work will be of interest to biochemists and biophysicists interested in the conformation-function relationship of intrinsically disordered proteins.

Reviewed by eLife

Early steps of protein disaggregation by Hsp70 chaperone and class B J-domain proteins are shaped by Hsp110

1. Wiktoria Sztangierska
2. Hubert Wyszkowski
3. Maria Pokornowska
4. Klaudia Kochanowicz
5. Michal Rychłowski
6. Krzysztof Liberek
7. Agnieszka Kłosowska

• Curated by eLife

  eLife assessment

  This study provides an important insight into the mechanisms of cooperation between Hsp70 and its cochaperones during reactivation of aggregated proteins. Based on convincing evidence, the authors demonstrate that the co-chaperone Hsp110 boosts disaggregation activity by enhancing 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