Biochemistry

Cardiolipin deficiency disrupts electron transport chain to drive steatohepatitis

1. Marisa J Brothwell
2. Guoshen Cao
3. J Alan Maschek
4. Annelise M Poss
5. Alek D Peterlin
6. Liping Wang
7. Talia B Baker
8. Justin L Shahtout
9. Piyarat Siripoksup
10. Quentinn J Pearce
11. Jordan M Johnson
12. Fabian M Finger
13. Alexandre Prola
14. Sarah A Pellizzari
15. Gillian L Hale
16. Allison M Manuel
17. Shinya Watanabe
18. Edwin R Miranda
19. Kajsa E Affolter
20. Trevor S Tippetts
21. Linda S Nikolova
22. Ran Hee Choi
23. Stephen T Decker
24. Mallikarjun Patil
25. J Leon Catrow
26. William L Holland
27. Sara M Nowinski
28. Daniel S Lark
29. Kelsey H Fisher-Wellman
30. Patrice N Mimche
31. Kimberley J Evason
32. James E Cox
33. Scott A Summers
34. Zach Gerhart-Hines
35. Katsuhiko Funai

• Curated by eLife

  eLife Assessment

  This paper reports on a correlation between diminished cardiolipin content and the severity of steatohepatitis in human subjects. This is supported further by experimental evidence from mice in which the gene encoding a key enzyme in cardiolipin synthesis has been compromised in the liver. The correlations established between lipidology, mitochondrial function, and the induction of respiration and oxidative stress are notable and will be useful to researchers in the field. However, given that the causal relationship between lipid perturbation and the progression of steatohepatitis implied in the title has not been tested experimentally, the evidence supporting the paper's key conclusion is incomplete.

Reviewed by eLife

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

The Structural Dynamics of IRE1 and its Interaction with Unfolded Peptides

1. Elena Spinetti
2. G Elif Karagöz
3. Roberto Covino

• Curated by eLife

  eLife Assessment

  In this important study, the authors conducted atomistic molecular dynamics simulations to probe the interactions between IRE and unfolded peptides. The results help reconcile contradicting experimental findings in the literature and offer mechanistic insights into the activation of the unfolded protein response. The level of evidence is considered solid, although the use of enhanced sampling and more quantitative analysis would further strengthen 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

Membrane curvature regulates Ups1 dependent phosphatidic acid transfer across lipid bilayers

1. Fereshteh Sadeqi
2. Dexin Dong
3. Kai Stroh
4. Marian Vache
5. Jutta Metz
6. Dietmar Riedel
7. Andreas Janshoff
8. Herre Jelger Risselada
9. Caroline Kolenda
10. Michael Meinecke

• Curated by eLife

  eLife Assessment

  This fundamental study combines in vitro reconstitution experiments and molecular dynamics simulations to elucidate how membrane lipids are transported from the outer to the inner membrane of mitochondria. The authors provide convincing evidence that a positive membrane curvature is critical for membrane lipid extraction. The work will be of broad interest to cell biologists and biochemists.

Reviewed by eLife

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