Biochemistry

Cardiolipin deficiency disrupts electron transport chain and drives 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 Evason
32. James E Cox
33. Scott A Summers
34. Zach Gerhart-Hines
35. Katsuhiko Funai

• Curated by eLife

  eLife Assessment

  This revised manuscript retreats from the original claim of establishing a causal link between cardiolipin deficiency and the progression from steatotic liver disease to steatohepatitis and instead advances a more limited mechanistic conclusion: that cardiolipin deficiency perturbs electron transport and promotes electron leak from the mitochondrial respiratory chain. The experimental evidence supporting this revised claim is now solid, and the potential for increased electron leak to contribute to liver pathophysiology is demonstrated. However, absent evidence that cardiolipin deficiency is causally upstream of disease progression, the overall significance of the work remains limited. While the study provides a convincing analysis of mitochondrial bioenergetics, the narrowing of its central claim diminishes its impact relative to that proposed in the original submission.

Reviewed by eLife

Dynamic assembly of malate dehydrogenase–citrate synthase multienzyme complex in the mitochondria

1. Joy Omini
2. Inga Krassovskaya
3. Taiwo Adeolu Dele-Osibanjo
4. Connor Pedersen
5. Toshihiro Obata

• Curated by eLife

  eLife Assessment

  This important study provides novel information on multi-enzyme complexes, known as metabolons, that form between sequential enzymes in a metabolic pathway. Using an innovative NanoBiT split-luciferase system, the authors present compelling evidence that malate dehydrogenase (MDH1) and citrate synthase (CIT1) dynamically associate under different metabolic conditions in Saccharomyces cerevisiae. The findings suggest the dynamic MDH1-CIT1 interaction facilitates control of TCA pathway flux rate.

Reviewed by eLife

Single-step in vitro reconstitution of the Escherichia coli ribosome mediated by two GTPase factors, EngA and ObgE

1. Aya Sato
2. Weng Yu Lai
3. Yusuke Sakai
4. Keiko Masuda
5. Yoshihiro Shimizu

• Curated by eLife

  eLife Assessment

  This is a valuable study presenting convincing data indicating that the bacterial GTPases EngA and ObgE enable single-step reconstitution of functional 50S ribosomal subunits under near-physiological conditions. The study elegantly bridges the gap between the non-physiological aspects of the previous two-step reconstitution method and the extract-dependent iSAT system to enable assembly of highly functional ribosomes under translation-compatible conditions. The reported findings represent substantial progress towards achieving a bottom-up reconstruction of the translation machinery from synthetic parts.

Reviewed by eLife

Integrating computational protein structure predictions and genetic dependencies yields an atlas of human multi-protein complexes (AHMPC)

1. Michael Uckelmann
2. Daniel Alvarez Salmoral
3. Carmen Maiella
4. Onno Bleijerveld
5. Ceri Zwart
6. Eric Marcus
7. Joren Brunekreef
8. Jonas Teuwen
9. Roderick Beijersbergen
10. Anastassis Perrakis

Reviewed by Review Commons

Intraflagellar transport protein IFT172 contains a C-terminal ubiquitin-binding U-box-like domain involved in ciliary signaling

1. Nevin K Zacharia
2. Stefanie Kuhns
3. Niels Boegholm
4. Anni Christensen
5. Jiaolong Wang
6. Narcis A Petriman
7. Anna Lorentzen
8. Jindriska L Fialova
9. Lucie Menguy
10. Sophie Saunier
11. Søren Tvorup Christensen
12. Jens S Andersen
13. Sagar Bhogaraju
14. Esben Lorentzen

• Curated by eLife

  eLife Assessment

  This important work advances our understanding of intraflagellar transport, ciliogenesis, and ciliary-based signaling, by identifying the interactions of IFT172 with IFT-A components, ubiquitin-binding, and ubiquitination, mediated by IFT172 C-terminus and its role in ciliogenesis and ciliary signaling. The evidence supporting the findings is convincing. This paper will be of interest to cell biologists and biochemists, especially those working on cilia and signaling.

Reviewed by eLife

Purified zymogens reveal mechanisms of snake venom metalloproteinase auto-activation

1. Sophie Hall
2. Iara Aime Cardoso
3. Mark C Wilkinson
4. Maria Molina Carretero
5. Srikanth Lingappa
6. Bronwyn Rand
7. Dakang Shen
8. Johara Boldrini-França
9. Richard Stenner
10. Stefanie Kate Menzies
11. Georgia Balchin
12. Konrad Kamil Hus
13. Renaud Vincentelli
14. Andrew Mumford
15. Alastair Poole
16. Nicholas R Casewell
17. Imre Berger
18. Christiane Schaffitzel

• Curated by eLife

  eLife Assessment

  In this useful paper, the authors present a comprehensive method for the purification of recombinant Snake Venom Metalloproteinases (SVMPs) using the MultiBac expression system, explain the self-activation of the enzymes by Zn2+ incubation, and establish high-throughput screening (HTS) techniques. The authors addressed a key problem: producing a substantial amount of pure and enzymatically active SVMPs required for structural and functional studies. Altogether, this work builds a solid foundation for the large-scale production of active SVMPs for future biochemical and structural characterization as well as for drug discovery, albeit leaving certain caveats about the universal applicability of the described methodology for the production of any recombinant SVMPs.

Reviewed by eLife

Nuclear CK1δ as a critical determinant of PER:CRY complex dynamics and circadian period

1. Fidel Emmanuel Serrano
2. Daniela Marzoll
3. Bianca Ruppert
4. Axel CR Diernfellner
5. Michael Brunner

• Curated by eLife

  eLife Assessment

  This valuable study examines the subcellular dynamics of the mammalian circadian clock proteins PER2, CRY1, and CK1, providing solid evidence that CK1 modulates the PER2-CRY1 interaction and drives the cytoplasmic localization of PER2 complexes. This could play a key role in modulating transcriptional repression by PER2, CRY1, and CK that contributes to the molecular circadian clock. There are minor concerns regarding the overexpression of the clock proteins in this study.

  [Editors' note: this paper was previously reviewed by another journal.]

Reviewed by eLife

The structure of Egalitarian in complex with the K10 mRNA localization signal reveals a modular binding surface required for function

1. Zebin Hong
2. Li Jin
3. Jonas Mühle
4. Fulvia Bono

• Curated by eLife

  eLife Assessment

  This manuscript has convincing data that provides a high-resolution structure of the Egl-RNA complex. The findings are important to understand the formation, stability, and interactions of this complex. However, the manuscript could be improved by conducting a rigorous statistical analysis, a deeper understanding of apparent discrepancies in the stoichiometric Egl-to-RNA ratio, and exploring the specificity of this complex using a more diverse set of control RNAs.

Reviewed by eLife

Structural dynamics of IRE1 and its interaction with unfolded peptides

1. Elena Spinetti
2. Grzegorz Ścibisz
3. Gülsün Elif Karagöz
4. 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 atomistic molecular dynamics simulations performed are solid, leading to convincing conclusions that are partly supported by experimental validations. The use of unbiased molecular dynamics simulations, while appropriate for the current system due to its complexity, limits the time scale of events that can be observed and therefore the proposed mechanism of recognition merits further confirmation by future studies.

Reviewed by eLife

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

1. Xiaoyu Yu
2. Yuanjun He
3. Thedore 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 compelling. This manuscript will be of interest to scientists focusing on mechanisms of transcriptional regulation.

Reviewed by eLife