Biochemistry

Towards a unified molecular mechanism for ligand-dependent activation of NR4A-RXR heterodimers

1. Xiaoyu Yu
2. Yuanjun He
3. Theodore M Kamenecka
4. Douglas J Kojetin

• Curated by eLife

  eLife Assessment

  This important study investigated whether the nuclear receptor Nur77 is regulated by a non-canonical mechanism of ligand-induced disruption of its interaction with RXRg, similar to the family member Nurr1. The overall evidence is solid, but additional mechanisms that have not been fully explored in this study might contribute as well. This manuscript will be of interest to scientists focusing on mechanisms of transcriptional regulation.

Reviewed by eLife

Dual-specific autophosphorylation of kinase IKK2 enables phosphorylation of substrate IκBα through a phosphoenzyme intermediate

1. Prateeka Borar
2. Tapan Biswas
3. Ankur Chaudhuri
4. Pallavi T Rao
5. Swasti Raychaudhuri
6. Tom Huxford
7. Saikat Chakrabarti
8. Gourisankar Ghosh
9. Smarajit Polley

• Curated by eLife

  eLife Assessment

  This study presents fundamental findings that could redefine the specificity and mechanism of action of the well-studied Ser/Thr kinase IKK2 (a subunit of inhibitor of nuclear factor kappa-B kinase (IkB) that propagates cellular response to inflammation). Solid evidence supports the claim that IKK2 exhibits dual specificity that allows tyrosine autophosphorylation and the authors further show that auto-phosphorylated IKK2 is involved in an unanticipated relay mechanism that transfers phosphate from an IKK2 tyrosine onto the IkBa substrate. The findings are a starting point for follow-up studies to confirm the unexpected mechanism and further pursue functional significance.

Reviewed by eLife

Energetic and structural control of polyspecificity in a multidrug transporter

1. Silas T. Miller
2. Katherine A. Henzler-Wildman
3. Srivatsan Raman

Reviewed by PREreview

Growth inhibitory factor/metallothionein-3 is a sulfane sulfur-binding protein

1. Yasuhiro Shinkai
2. Yunjie Ding
3. Toru Matsui
4. George Devitt
5. Masahiro Akiyama
6. Tang-Long Shen
7. Motohiro Nishida
8. Tomoaki Ida
9. Takaaki Akaike
10. Sumeet Mahajan
11. Jon M Fukuto
12. Yasuteru Shigeta
13. Yoshito Kumagai

• Curated by eLife

  eLife Assessment

  This valuable work provides solid evidence that a neuronal metallothionein, GIF/MT-3, incorporates metal-persulfide clusters. A variety of well-designed assays support the authors' hypothesis, revealing that sulfane sulfur is released from MT-3. However, the sufane sulfur content in the canonical induced MT-1 and MT-2 has not been demonstrated. Thus, the biological role of the persulfidated form is not yet clearly defined. There are caveats to the findings that limit the study, but the work will nevertheless prompt major follow-up work.

Reviewed by eLife

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

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

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