Biochemistry

The alternative oxidase reconfigures the larval mitochondrial electron transport system to accelerate growth and development in Drosophila melanogaster

1. Geovana S Garcia
2. Murilo F Othonicar
3. Antonio Thiago P Campos
4. Eric A Kilbourn
5. Kênia C Bícego
6. Johannes Lerchner
7. Jason M Tennessen
8. Marcos T Oliveira

• Curated by eLife

  eLife Assessment

  The findings in this manuscript are important because they demonstrate the key role of metabolism in insect development. The data were collected and analyzed using solid and validated methodologies, but the evidence is incomplete, as the extent of the involvement of AOX activity in vivo and in physiological conditions is not addressed. This manuscript will be of interest for the fields of mitochondrial bioenergetics, metabolism and development.

Reviewed by eLife

Epitope Sequence and Modification Fingerprints of Anti-Aβ Antibodies

1. Ivan Talucci
2. Timon Leske
3. Hans-Wolfgang Klafki
4. Mohammed Mehedi Hassan
5. Annik Steiert
6. Barbara Morgado
7. Sebastian Bothe
8. Lars van Werven
9. Thomas Liepold
10. Jochen Walter
11. Hermann Schindelin
12. Jens Wiltfang
13. Oliver Wirths
14. Olaf Jahn
15. Hans-Michael Maric

• Curated by eLife

  eLife Assessment

  Antibodies that selectively bind distinct amyloid-beta variants are vital tools for Alzheimer's disease research. This valuable manuscript aims to delineate the epitope specificity in a panel of anti-amyloid-beta antibodies, including some with clinical relevance. The experiments were rigorously conducted, employing an interesting combination of established and state-of-the-art methodologies, yielding mostly robust findings. While the data regarding antibody sequence preferences for distinct amyloid-beta regions and aggregation states are convincing, a thorough revision of the manuscript would help to highlight the key results.

Reviewed by eLife

Targeted protein degradation by KLHDC2 ligands identified by high-throughput screening

1. Han Zhou
2. Tonglian Zhou
3. Wenli Yu
4. Liping Liu
5. Yeonjin Ko
6. Kristen A Johnson
7. Ian A Wilson
8. Peter G Schultz
9. Michael J Bollong

• Curated by eLife

  eLife Assessment

  This valuable study aims to advance the toolkit of small molecules used for approaches to targeted protein degradation for research and therapeutic applications. The authors provide solid data demonstrating the use of a high-throughput screen of small molecules to target a specific E3 ligase, KLHDC2 (Kelch-like homology domain containing protein 2); the resulting compounds then form the basis for new PROTAC (proteolysis targeting chimera) reagents. The strength of the work lies in expanding the PROTAC reagent inventory. The current work would be strengthened further by confirming that the PROTAC's activity is dependent on KLHDC2 and by a more thorough examination of off-target effects in cellular applications.

Reviewed by eLife

One-carbon metabolism enzyme Ahcy is a redox sensor that modulates gene expression to protect against light stress-induced retinal degeneration

1. Sarah C. Stanhope
2. Kratika Singhal
3. Nicolás M. Morato
4. Yunfei Feng
5. Gaoya Meng
6. Makayla N. Marlin
7. Claudia C. Kotanko
8. Madolyn M. Jarrett
9. Andrew D. Mesecar
10. Graham R. Cooks
11. Vikki M. Weake

Reviewed by PREreview

Shifting the PPARγ conformational ensemble towards a transcriptionally repressive state improves covalent inhibitor efficacy

1. Liudmyla Arifova
2. Brian S MacTavish
3. Zane Laughlin
4. Mithun Nag Karadi Giridhar
5. Jinsai Shang
6. Min-Hsuan Li
7. Xiaoyu Yu
8. Di Zhu
9. Theodore M Kamenecka
10. Douglas J Kojetin

• Curated by eLife

  eLife Assessment

  This manuscript presents a fundamental advance in our understanding of nuclear receptor pharmacology by expanding on previous work demonstrating dual ligand occupancy in the peroxisome proliferator-activated receptor-gamma (PPARγ). Using a compelling combination of biophysical, structural, and cellular approaches, the authors show that covalent inhibitors with inverse agonist activities modulate receptor conformation to permit co-binding with additional ligands, leading to a finely tuned transcriptional response. The data support a model of proximal, bi-directional allostery that challenges traditional views of nuclear receptor regulation. These findings will be of broad interest to researchers in structural biology, transcriptional control, and drug discovery.

Reviewed by eLife

In silico discovery of nanobody binders to a G-protein coupled receptor using AlphaFold-Multimer

1. Edward P. Harvey
2. Jeffrey S. Smith
3. Joseph D. Hurley
4. Alyana Granados
5. Ernst W. Schmid
6. Jason G. Liang-Lin
7. Steffanie Paul
8. Emily M. Meara
9. Matthew P. Ferguson
10. Victor G. Calvillo-Miranda
11. Debora S. Marks
12. Johannes C. Walter
13. Andrew C. Kruse
14. Katherine J. Susa

Reviewed by Arcadia Science

Fibroblast growth factor 21 regulates neuromuscular junction innervation through HDAC4 in denervation-induced skeletal muscle atrophy

1. Lirong Zheng
2. Takashi Sasaki
3. Liyang Ni
4. Yu Takahashi
5. Yoshio Yamauchi
6. Makoto Shimizu
7. Sato Ryuichiro

Reviewed by preLights

Development of D-box peptides to inhibit the anaphase-promoting complex/cyclosome

1. Rohan Eapen
2. Cynthia Okoye
3. Christopher Stubbs
4. Marianne Schimpl
5. Thomas Tischer
6. Eileen J Fisher
7. Maria Zacharopoulou
8. Fernando Ferrer
9. David Barford
10. David R Spring
11. Catherine Lindon
12. Christopher Phillips
13. Laura S Itzhaki

• Curated by eLife

  eLife Assessment

  The manuscript represents a fundamental advance in designing peptide inhibitors targeting Cdc20, a key activator and substrate-recognition subunit of the APC/C ubiquitin ligase. Supported by compelling biophysical and cellular evidence, the study lays a strong foundation for future developments in degron-based therapeutics. The revised manuscript has been strengthened by additional clarifications and data that address prior reviewer concerns. The work provides a robust framework for developing tools to manipulate protein degradation and will be of broad interest to researchers in protein engineering, cell cycle regulation, and targeted protein degradation.

Reviewed by eLife

Identification of the Regulatory Elements and Protein Substrates of Lysine Acetoacetylation

1. Qianyun Fu
2. Terry Nguyen
3. Bhoj Kumar
4. Parastoo Azadi
5. Y George Zheng

• Curated by eLife

  eLife Assessment

  This useful study reports a method to detect and analyze a novel post-translational modification, lysine acetoacetylation (Kacac), finding it regulates protein metabolism pathways. The study unveils epigenetic modifiers involved in placing this mark, including key histone acetyltransferases such as p300, and concomitant HDACs, which remove the mark. Proteomic and bioinformatics analysis identified many human proteins with Kacac sites, potentially suggesting broad effects on cellular processes and disease mechanisms. While the data presented are solid, the functional validation of the sites would add significantly to the manuscript's description of this modification; the study will be of interest to those studying protein and metabolic regulation.

Reviewed by eLife

Solubilization of Membrane Proteins using designed protein WRAPS

1. Ljubica Mihaljević
2. David E. Kim
3. Helen E. Eisenach
4. Pooja D. Bandawane
5. Andrew J. Borst
6. Alexis Courbet
7. Everton Bettin
8. Qiushi Liu
9. Connor Weidle
10. Sagardip Majumder
11. Xinting Li
12. Mila Lamb
13. Analisa Nicole Azcárraga Murray
14. Rashmi Ravichandran
15. Elizabeth C. Williams
16. Shuyuan Hu
17. Lynda Stuart
18. Linda Grillová
19. Nicholas R. Thomson
20. Pengxiang Chang
21. Melissa J. Caimano
22. Kelly L. Hawley
23. Neil P. King
24. David Baker

Reviewed by Rapid Reviews Infectious Diseases