Biochemistry

Dithiothreitol causes toxicity in C. elegans by modulating the methionine–homocysteine cycle

1. Gokul G
2. Jogender Singh

• Curated by eLife

  Evaluation Summary:

  Thiol agents, such as dithiothreitol (DTT), are toxic to many species, but the mechanisms of toxicity is incompletely understood. In this work, the authors use the animal C. elegans, a small worm, to propose a new mechanisms for how DTT causes organismal growth arrest. Specifically, they suggest that DTT causes reduction in the key molecule S-adenosyl methionine (SAM), which is used as a methyl donor to modify proteins, lipid, and/or other macromolecules. The genetic and supplementation experiments by the authors are compelling, but no direct evidence is provided that SAM levels are indeed lower following exposure of C. elegans to DTT.

  (This preprint has been reviewed by eLife. We include the public reviews from the reviewers here; the authors also receive private feedback with suggested changes to the manuscript. Reviewer #1 agreed to share their name with the authors.)

Reviewed by eLife

Structural basis for the in vitro efficacy of nirmatrelvir against SARS-CoV-2 variants

1. Samantha E. Greasley
2. Stephen Noell
3. Olga Plotnikova
4. RoseAnn Ferre
5. Wei Liu
6. Ben Bolanos
7. Kimberly Fennell
8. Jennifer Nicki
9. Tim Craig
10. Yuao Zhu
11. Al E. Stewart
12. Claire M. Steppan

Reviewed by ScreenIT

Glypican-1 drives unconventional secretion of fibroblast growth factor 2

1. Carola Sparn
2. Eleni Dimou
3. Annalena Meyer
4. Roberto Saleppico
5. Sabine Wegehingel
6. Matthias Gerstner
7. Severina Klaus
8. Helge Ewers
9. Walter Nickel

• Curated by eLife

  Evaluation Summary:

  FGF2 moves directly from the cytoplasm through the plasma membrane in a reaction driven by its subsequent high affinity binding to cell surface heparan sulfate proteoglycans. This study concludes that Glypican-1 is the principal proteoglycan involved, possibly involving a unique tri-sulfated disaccharide binding site in close proximity to the cell surface. While the role of Glypican-1 appears unique to FGF2 rather than part of a generalized direct secretion mechanism, the observations highlight the complexity and significance of proteoglycan variation. The work is well done and generally convincing, but additional support for the authors' conclusion that a specific glycan structure in GPC1 is a specific ligand for FGF2 is required.

  (This preprint has been reviewed by eLife. We include the public reviews from the reviewers here; the authors also receive private feedback with suggested changes to the manuscript. The reviewers remained anonymous to the authors.)

Reviewed by eLife

Structural and functional impact by SARS-CoV-2 Omicron spike mutations

1. Jun Zhang
2. Yongfei Cai
3. Christy L. Lavine
4. Hanqin Peng
5. Haisun Zhu
6. Krishna Anand
7. Pei Tong
8. Avneesh Gautam
9. Megan L. Mayer
10. Sophia Rits-Volloch
11. Shaowei Wang
12. Piotr Sliz
13. Duane R. Wesemann
14. Wei Yang
15. Michael S. Seaman
16. Jianming Lu
17. Tianshu Xiao
18. Bing Chen

Reviewed by ScreenIT

Molecular basis of SARS-CoV-2 Omicron variant receptor engagement and antibody evasion and neutralization

1. Qin Hong
2. Wenyu Han
3. Jiawei Li
4. Shiqi Xu
5. Yifan Wang
6. Zuyang Li
7. Yanxing Wang
8. Chao Zhang
9. Zhong Huang
10. Yao Cong

Reviewed by ScreenIT

Towards a molecular mechanism underlying mitochondrial protein import through the TOM and TIM23 complexes

1. Holly C Ford
2. William J Allen
3. Gonçalo C Pereira
4. Xia Liu
5. Mark Simon Dillingham
6. Ian Collinson

• Curated by eLife

  Evaluation Summary:

  This study employs a novel bioluminescence-based technique to analyze the import of precursor proteins into the mitochondrial matrix in real time. This is an innovative technical advance that can provide mechanistic detail on the kinetic steps of mitochondrial protein import. It has potential applications in other membrane protein transport systems and it could be applicable to studies in applied science such as screening for drugs targeting the mitochondrial import apparatus.

  (This preprint has been reviewed by eLife. We include the public reviews from the reviewers here; the authors also receive private feedback with suggested changes to the manuscript. Reviewer #2 and Reviewer #3 agreed to share their name with the authors.)

Reviewed by eLife

Autoinhibition and regulation by phosphoinositides of ATP8B1, a human lipid flippase associated with intrahepatic cholestatic disorders

1. Thibaud Dieudonné
2. Sara Abad Herrera
3. Michelle Juknaviciute Laursen
4. Maylis Lejeune
5. Charlott Stock
6. Kahina Slimani
7. Christine Jaxel
8. Joseph A Lyons
9. Cédric Montigny
10. Thomas Günther Pomorski
11. Poul Nissen
12. Guillaume Lenoir

• Curated by eLife

  Evaluation Summary:

  This manuscript reports the first high-resolution structure of the P4 flippase ATP8B1, which is associated with intrahepatic cholestatic disorder in humans. Using biochemical studies guided by the structure, the authors demonstrate ATP8B1's autoinhibition mechanism, its regulation by lipids and phosphorylation, and a plausible mechanism of disease-associated mutation. These results are an important contribution to the expanding literature in membrane protein dynamics and function.

  (This preprint has been reviewed by eLife. We include the public reviews from the reviewers here; the authors also receive private feedback with suggested changes to the manuscript. Reviewer #3 agreed to share their name with the authors.)

Reviewed by eLife

Structure-Based Identification of Naphthoquinones and Derivatives as Novel Inhibitors of Main Protease M ^pro and Papain-like Protease PL ^pro of SARS-CoV-2

1. Lucianna H. Santos
2. Thales Kronenberger
3. Renata G. Almeida
4. Elany B. Silva
5. Rafael E. O. Rocha
6. Joyce C. Oliveira
7. Luiza V. Barreto
8. Danielle Skinner
9. Pavla Fajtová
10. Miriam A. Giardini
11. Brendon Woodworth
12. Conner Bardine
13. André L. Lourenço
14. Charles S. Craik
15. Antti Poso
16. Larissa M. Podust
17. James H. McKerrow
18. Jair L. Siqueira-Neto
19. Anthony J. O’Donoghue
20. Eufrânio N. da Silva Júnior
21. Rafaela S. Ferreira

Reviewed by ScreenIT

Structural basis of SARS-CoV-2 Omicron immune evasion and receptor engagement

1. Matthew McCallum
2. Nadine Czudnochowski
3. Laura E. Rosen
4. Samantha K. Zepeda
5. John E. Bowen
6. Alexandra C. Walls
7. Kevin Hauser
8. Anshu Joshi
9. Cameron Stewart
10. Josh R. Dillen
11. Abigail E. Powell
12. Tristan I. Croll
13. Jay Nix
14. Herbert W. Virgin
15. Davide Corti
16. Gyorgy Snell
17. David Veesler

Reviewed by ScreenIT

Mapping the allosteric effects that define functional activity of SARS-CoV-2 specific antibodies

1. Nikhil K. Tulsian
2. Palur V. Raghuvamsi
3. Xinlei Qian
4. Gu Yue
5. Bhuvaneshwari D/O Shunmuganathan
6. Firdaus Samsudin
7. Wong Yee Hwa
8. Lin Jianqing
9. Kiren Purushotorman
10. Mary M. Kozma
11. Bei Wang
12. Julien Lescar
13. Cheng-I Wang
14. Ganesh S. Anand
15. Peter J. Bond
16. Paul A. MacAry

Reviewed by ScreenIT