Biochemistry

Biochemical and structural insights into the auto-inhibited state of Mical1 and its activation by Rab8

1. Amrita Rai
2. Petra Janning
3. Ingrid R Vetter
4. Roger S Goody

• Curated by eLife

  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.

Reviewed by eLife

Distinct mechanisms of inhibition of Kv2 potassium channels by tetraethylammonium and RY785

1. Shan Zhang
2. Robyn Stix
3. Esam A Orabi
4. Nathan Bernhardt
5. José D Faraldo-Gómez

• Curated by eLife

  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.

Reviewed by eLife

Malaria parasites require a divergent heme oxygenase for apicoplast gene expression and biogenesis

1. Amanda Mixon Blackwell
2. Yasaman Jami-Alahmadi
3. Armiyaw S Nasamu
4. Shota Kudo
5. Akinobu Senoo
6. Celine Slam
7. Kouhei Tsumoto
8. James A Wohlschlegel
9. Jose Manuel Martinez Caaveiro
10. Daniel E Goldberg
11. Paul A Sigala

• Curated by eLife

  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.

Reviewed by eLife

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

Elucidating the kinetic and thermodynamic insight into regulation of glycolysis by lactate dehydrogenase and its impact on tricarboxylic acid cycle and oxidative phosphorylation in cancer cells

1. Siying Zeng
2. Yuqi Wang
3. Minfeng Ying
4. Chengmeng Jin
5. Chang Ying
6. Di Wang
7. Hao Wu
8. Xun Hu

• Curated by eLife

  eLife assessment

  This study presents an assessment of the effect of lactate dehydrogenase (LDH) inhibition on the activity of glycolysis and tricarboxylic acid cycle. The data were collected and analyzed using solid and validated methodology. This paper makes a useful contribution to the field as it considers a control analysis of LDH flux.

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