Biochemistry

Structural analysis of the dynamic ribosome-translocon complex

1. Aaron JO Lewis
2. Frank Zhong
3. Robert J Keenan
4. Ramanujan S Hegde

• Curated by eLife

  eLife assessment

  This landmark work by Lewis and Hegde represents the most significant breakthrough in membrane and secretory biogenesis in recent years. Their work reveals with outstanding clarity how nascent transmembrane segments can pass through the gate of Sec61 into the ER membrane through the coordinated motions of a conformationally and compositionally dynamic machine. Among many other insights, the authors discovered how a new factor, RAMP4, contributes to the formation and function of the lateral gate for certain substrates. The technical quality of the work is exceptional, setting the bar appropriately high.

Reviewed by eLife

Structural and dynamic changes in P-Rex1 upon activation by PIP3 and inhibition by IP4

1. Sandeep K Ravala
2. Sendi Rafael Adame-Garcia
3. Sheng Li
4. Chun-Liang Chen
5. Michael A Cianfrocco
6. J Silvio Gutkind
7. Jennifer N Cash
8. John JG Tesmer

• Curated by eLife

  eLife assessment

  This important study contributes insights into the regulatory mechanisms of a protein governing cell migration at the membrane. The integration of approaches revealing protein structure and dynamics provides convincing data for a model of regulation and suggests a new allosteric role for a solubilized phospholipid headgroup. The work will be interesting to researchers focusing on signaling mechanisms, cell motility, and cancer metathesis.

Reviewed by eLife

Targeting protein-ligand neosurfaces using a generalizable deep learning approach

1. Anthony Marchand
2. Stephen Buckley
3. Arne Schneuing
4. Martin Pacesa
5. Pablo Gainza
6. Evgenia Elizarova
7. Rebecca M. Neeser
8. Pao-Wan Lee
9. Luc Reymond
10. Maddalena Elia
11. Leo Scheller
12. Sandrine Georgeon
13. Joseph Schmidt
14. Philippe Schwaller
15. Sebastian J. Maerkl
16. Michael Bronstein
17. Bruno E. Correia

Reviewed by PREreview

ESAT-6 undergoes self-association at phagosomal pH and an ESAT-6-specific nanobody restricts M. tuberculosis growth in macrophages

1. Timothy A Bates
2. Mila Trank-Greene
3. Xammy Huu Wrynla
4. Aidan Anastas
5. Sintayehu K Gurmessa
6. Ilaria R Merutka
7. Shandee D Dixon
8. Anthony Shumate
9. Abigail R Groncki
10. Matthew AH Parson
11. Jessica R Ingram
12. Eric Barklis
13. John E Burke
14. Ujwal Shinde
15. Hidde L Ploegh
16. Fikadu G Tafesse

• Curated by eLife

  eLife assessment

  This useful study investigates two secreted Mycobacterium tuberculosis proteins, ESAT-6 and CFP10, using biochemical assays, including a Biolayer Interferometry assay. Solid experimental evidence demonstrates that ESAT-6 forms a tight interaction with CFP10 as a heterodimer at neutral pH and that ESAT-6 also forms a homodimer at acidic pH. Additional, more definitive evidence is required to describe how these proteins disrupt the phagosomal membrane. While improved compared to a previous version, the revised manuscript did not address these concerns adequately.

Reviewed by eLife

Mutational profiling of SARS-CoV-2 papain-like protease reveals requirements for function, structure, and drug escape

1. Xinyu Wu
2. Margareta Go
3. Julie V. Nguyen
4. Nathan W. Kuchel
5. Bernadine G. C. Lu
6. Kathleen Zeglinski
7. Kym N. Lowes
8. Dale J. Calleja
9. Jeffrey P. Mitchell
10. Guillaume Lessene
11. David Komander
12. Matthew E. Call
13. Melissa J. Call

Reviewed by PREreview

Stoichiometric 14-3-3ζ binding promotes phospho-Tau microtubule dissociation and reduces aggregation and condensation

1. Janine Hochmair
2. Maxime C. M. van den Oetelaar
3. Leandre Ravatt
4. Lisa Diez
5. Lenne J. M. Lemmens
6. Renata Ponce-Lina
7. Rithika Sankar
8. Maximilian Franck
9. Gesa Nolte
10. Ekaterina Semenova
11. Satabdee Mohapatra
12. Christian Ottmann
13. Luc Brunsveld
14. Susanne Wegmann

Reviewed by preLights

7,8-Dihydroxyflavone is a direct inhibitor of human and murine pyridoxal phosphatase

1. Marian Brenner
2. Christoph Zink
3. Linda Witzinger
4. Angelika Keller
5. Kerstin Hadamek
6. Sebastian Bothe
7. Martin Neuenschwander
8. Carmen Villmann
9. Jens Peter von Kries
10. Hermann Schindelin
11. Elisabeth Jeanclos
12. Antje Gohla

• Curated by eLife

  eLife assessment

  Following small molecule screens, this study provides convincing evidence that 7,8 dihydroxyflavone (DHF) is a competitive inhibitor of pyridoxal phosphatase. These results are important since they offer an alternative mechanism for the effects of 7,8 dihdroxyflavone in cognitive improvement in several mouse models. This paper is also significant due to the interest in the phosphatases and neurodegeneration fields.

Reviewed by eLife

Human pannexin 1 channel is not phosphorylated by Src tyrosine kinase at Tyr199 and Tyr309

1. Zheng Ruan
2. Junuk Lee
3. Yangyang Li
4. Juan Du
5. Wei Lü

• Curated by eLife

  eLife assessment

  The current manuscript re-examines an established claim in the literature that human PANX-1 is regulated by Src kinase phosphorylation at two tyrosine residues, Y199 and Y309. This issue is important for our understanding of Pannexin channel regulation. The authors present an extensive series of experiments that fail to detect PANX-1 phosphorylation at these sites. Although the authors' approach is more rigorous than the previous studies, this work relies primarily on negative results that are not unambiguously definitive; the work nonetheless provides a compelling reason for the field to reexamine conclusions drawn in earlier studies.

Reviewed by eLife

Redox regulation and dynamic control of brain-selective kinases BRSK1/2 in the AMPK family through cysteine-based mechanisms

1. George N Bendzunas
2. Dominic P Byrne
3. Safal Shrestha
4. Leonard A Daly
5. Sally O Oswald
6. Samiksha Katiyar
7. Aarya Venkat
8. Wayland Yeung
9. Claire E Eyers
10. Patrick A Eyers
11. Natarajan Kannan

• Curated by eLife

  eLife assessment

  This study provides fundamental new knowledge into the role of reversible cysteine oxidation and reduction in protein kinase regulation. The data provide convincing evidence that intra-molecular disulfide bonds serve a repressive regulatory role in the Brain Selective Kinases (BRSK) 1 & 2; part of the as yet understudied 'dark kinome'. The findings will be of broad interest to biochemists, structural biologists, and those interested in the rational design and development of next-generation kinase inhibitors.

Reviewed by eLife

Quantitative mapping of proteasome interactomes and substrates using ProteasomeID

1. Aleksandar Bartolome
2. Julia C Heiby
3. Domenico Di Fraia
4. Ivonne Heinze
5. Hannah Knaudt
6. Ellen Spaeth
7. Omid Omrani
8. Alberto Minetti
9. Maleen Hofmann
10. Joanna M Kirkpatrick
11. Therese Dau
12. Alessandro Ori

• Curated by eLife

  eLife assessment

  This study presents an important method and resource in cell lines and in mice for mass spectrometry-based identification of interactors of the proteasome, a multi-protein complex with a central role in protein turnover in almost all tissues and cell types. The method presented, including the experimental workflow and analysis pipeline, as well as the several lines of validation provided throughout, is convincing. Given the growing interest in protein aggregation and targeted protein degradation modalities, this work will be of interest to a broad spectrum of basic cell biologists and translational researchers.

Reviewed by eLife, preLights