Biochemistry

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

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

Blue-shifted ancyromonad channelrhodopsins for multiplex optogenetics

1. Elena G Govorunova
2. Oleg A Sineshchekov
3. Hai Li
4. Yueyang Gou
5. Hongmei Chen
6. Shuyuan Yang
7. Yumei Wang
8. Stephen Mitchell
9. Alyssa Palmateer
10. Leonid S Brown
11. François St-Pierre
12. Mingshan Xue
13. John L Spudich

• Curated by eLife

  eLife Assessment

  This important study describes newly identified light-gated ion channel homologs (channelrhodopsins, ChRs) in several protist species, with a primary focus on the biophysical characterization of ChRs of ancyromonads. The authors employed a powerful combination of bioinformatics, manual and automated patch-clamp electrophysiology, absorption spectroscopy, and flash photolysis. Additionally, they evaluated the applicability of the newly discovered anion-conducting ChRs in cortical neurons of mouse brain slices and in living C. elegans worms. The evidence supporting most of the claims is convincing and this work will be of interest to the microbial rhodopsin community and neuro- and cardioscientists utilizing optogenetics in their research.

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

Coupled equilibria of dimerization and lipid binding modulate SARS Cov 2 Orf9b interactions and interferon response

1. CJ San Felipe
2. Jyoti Batra
3. Monita Muralidharan
4. Shivali Malpotra
5. Durga Anand
6. Rachel Bauer
7. Kliment A Verba
8. Danielle L. Swaney
9. Nevan J. Krogan
10. Michael Grabe
11. James S. Fraser

• Curated by eLife

  eLife Assessment

  This important study demonstrates that lipid binding can regulate the dimerization state of the SARS-CoV2 Orf9b protein. The data from biophysical and cellular experiments, along with mathematical modeling, are convincing. However, this study can further benefit from more rigorous quantitative analyses and from resolving the role of dimerization in viral infection and host innate responses. This paper is broadly relevant to those studying coupled equilibria across all aspects of biology.

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