Biochemistry

Elevated ubiquitin phosphorylation by PINK1 contributes to proteasomal impairment and promotes neurodegeneration

1. Cong Chen
2. Tong-Yao Gao
3. Hua-Wei Yi
4. Yi Zhang
5. Tong Wang
6. Zhi-Ling Lou
7. Tao-Feng Wei
8. Yun-Bi Lu
9. Tingting Li
10. Chun Tang
11. Wei-Ping Zhang

• Curated by eLife

  eLife Assessment

  This study provides important insights into the role of polyUbiquitination in neurodegenerative diseases, elucidating how pUb promotes neurodegeneration by affecting proteasomal function. The findings not only offer a new perspective on the pathophysiology of neurodegenerative diseases but also provide potential targets for developing new therapeutic strategies. The results provide solid evidence to support the conclusions.

Reviewed by eLife

Conformational dynamics and asymmetry in multimodal inhibition of membrane-bound pyrophosphatases

1. Jianing Liu
2. Anokhi Shah
3. Xinyu Liu
4. Joshua L Wort
5. Yue Ma
6. Katie Hardman
7. Niklas G Johansson
8. Orquidea Ribeiro
9. Adam Brookfield
10. Alice Bowen
11. Jari Yli-Kauhaluoma
12. Henri Xhaard
13. Lars JC Jeuken
14. Adrian Goldman
15. Christos Pliotas
16. Keni Vidilaseris

• Curated by eLife

  eLife Assessment

  This important study uncovers the mechanism of inhibition of a membrane pyrophosphatase by non-hydrolyzable phosphonate substrate analogs. Convincing crystallography, EPR spectroscopy, and functional measurements support the presence of a distinct conformational equilibrium of TmPPase in solution, and further supports the notion of asymmetric inhibitor binding at the active site, while maintaining a symmetric conformation at the periplasmic interface.

Reviewed by eLife

Mapping Cryptic Phosphorylation Sites in the Human Proteome

1. Dino Gasparotto
2. Annarita Zanon
3. Valerio Bonaldo
4. Elisa Marchiori
5. Massimo Casagranda
6. Erika Di Domenico
7. Laura Copat
8. Tommaso Fortunato Asquini
9. Marta Rigoli
10. Sirio Vittorio Feltrin
11. Nuria Lopez Lorenzo
12. Graziano Lolli
13. Maria Pennuto
14. Jesùs R. Requena
15. Omar Rota Stabelli
16. Giovanni Minervini
17. Cristian Micheletti
18. Giovanni Spagnolli
19. Pietro Faccioli
20. Emiliano Biasini

Reviewed by Review Commons

Structural insights into heterohexameric assembly of epilepsy-related ligand–receptor complex LGI1–ADAM22

1. Takayuki Yamaguchi
2. Kei Okatsu
3. Masato Kubota
4. Ayuka Mitsumori
5. Atsushi Yamagata
6. Yuko Fukata
7. Masaki Fukata
8. Mikihiro Shibata
9. Shuya Fukai

• Curated by eLife

  eLife Assessment

  In this convincing work by Yamaguchi et al. the cryo-EM structure of the heterohexameric 3:3 LGI1-ADAM22 complex is presented. The findings suggest that LGI1 can cluster ADAM22 in a trimeric fashion. The clustering of cell surface proteins is important in controlling signaling in the nervous system. This new version of the manuscript has been improved substantially and the figures have been enhanced and clarified.

Reviewed by eLife

A broad-spectrum antibiotic targets multiple-drug-resistant bacteria with dual binding targets and no detectable resistance

1. Wenyan He
2. Xueting Huan
3. Yinchuan Li
4. Qisen Deng
5. Tao Chen
6. Wen Xiao
7. Yijun Chen
8. Lingman Ma
9. Nan Liu
10. Zhuo Shang
11. Zongqiang Wang

Reviewed by Rapid Reviews Infectious Diseases

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