Biophysics

Flexibility in PAM recognition expands DNA targeting in xCas9

1. Kazi A Hossain
2. Lukasz Nierzwicki
3. Modesto Orozco
4. Jacek Czub
5. Giulia Palermo

• Curated by eLife

  eLife Assessment

  This manuscript describes a fundamental investigation of the functioning of Cas9 and in particular on how variant xCas9 expands DNA targeting ability by an increase-flexibility mechanism. The authors provide compelling evidence to support their mechanistic models and the relevance of flexibility and entropy in recognition. This work can be of interest to a broad community of structural biophysicists, computational biologists, chemists, and biochemists.

Reviewed by eLife

PROTAC-induced protein structural dynamics in targeted protein degradation

1. Kingsley Y Wu
2. Ta I Hung
3. Chia-en A Chang

• Curated by eLife

  eLife Assessment

  This study provides important computational insights into the dynamics of PROTAC-induced degradation complexes, offering a convincing demonstration that differences in degradation efficacy can be linked to linker properties. The analyses address reproducibility considerations comprehensively, reinforcing the study's conclusions. Overall, these findings are significant for advancing cancer treatments and will be of broad interest to both biochemists and biophysicists.

Reviewed by eLife

Tension-induced suppression of allosteric conformational changes explains coordinated stepping of kinesin-1

1. Tsukasa Makino
2. Ryo Kanada
3. Teppei Mori
4. Ken-ichi Miyazono
5. Yuta Komori
6. Haruaki Yanagisawa
7. Shoji Takada
8. Masaru Tanokura
9. Masahide Kikkawa
10. Michio Tomishige

Reviewed by Review Commons

Mechanical stresses govern myoblast fusion and myotube growth

1. Yoann Le Toquin
2. Sushil Dubey
3. Aleksandra Ardaševa
4. Lakshmi Balasubramaniam
5. Emilie Delaune
6. Valérie Morin
7. Amin Doostmohammadi
8. Christophe Marcelle
9. Benoît Ladoux

Reviewed by preLights

Cell cycle and age-related modulations of mouse chromosome stiffness

1. Ning Liu
2. Wenan Qiang
3. Philip W Jordan
4. John F Marko
5. Huanyu Qiao

• Curated by eLife

  eLife Assessment

  This valuable paper describes the stiffness of meiotic chromosomes in both oocytes and spermatocytes. The authors identify differences in stiffness between meiosis I and II chromosomes, as well as an age-dependent increase in stiffness in meiosis I (and meiosis II) chromosomes, results that are highly significant for the field of chromosome biology. The report is, however, mostly descriptive and the mechanisms underlying age-dependent changes in chromosome stiffness remain unclear. The evidence suggesting that changes in stiffness are independent of cohesin, which is known to deteriorate with age, is still incomplete.

Reviewed by eLife

Probing the force-from-lipid mechanism with synthetic polymers

1. Miranda L Jacobs
2. Jan Steinkühler
3. Audra Lemley
4. Megan J Larmore
5. Taylor F Gunnels
6. Leo CT Ng
7. Stephanie M Cologna
8. Paul G DeCaen
9. Neha P Kamat

• Curated by eLife

  eLife Assessment

  Gating of mechanosensitive channels has been explained by the force-from-lipids model in which mechanical coupling of the channel protein to the plasma membrane transfers force from membrane tension to open the channel. In this important manuscript, the authors provide evidence for this mechanism in two different mechanically gated channels. The experiments were carried out in the same membranes, but the evidence is incomplete without a clear explanation of the relationship between measured mechanical parameters and membrane interfacial tension.

Reviewed by eLife

Mechanistic insight for T-cell exclusion by cancer-associated fibroblasts in human lung cancer

1. Joseph Ackermann
2. Chiara Bernard
3. Philemon Sirven
4. Helene Salmon
5. Massimiliano Fraldi
6. Martine D Ben Amar

• Curated by eLife

  eLife Assessment

  This is a valuable report of a spatially-extended model to study the complex interactions between immune cells, fibroblasts, and cancer cells, providing insights into how fibroblast activation can influence tumor progression. The model opens up new possibilities for studying fibroblast-driven effects in diverse settings, which is crucial for understanding potential tumor microenvironment manipulations that could enhance immunotherapy efficacy. While the results presented are convincing and follow logically from the model's assumptions, some of these assumptions, as acknowledged by the authors, may oversimplify certain aspects in light of complex experimental findings, system geometry, and general principles of active matter research. Nonetheless, the authors provide justification for their work as a meaningful step towards more comprehensive modeling approaches.

Reviewed by eLife

Wide transition-state ensemble as key component for enzyme catalysis

1. Gabriel E Jara
2. Francesco Pontiggia
3. Renee Otten
4. Roman V Agafonov
5. Marcelo A Martí
6. Dorothee Kern

• Curated by eLife

  eLife Assessment

  In this potentially important study, the authors report results of QM/MM simulations and kinetic measurements for the phosphoryl-transfer step in adenylate kinase. The results point to the mechanistic proposal that the transition state ensemble is broader in the most efficient form of the enzyme (i.e., in the presence of Mg2+ in the active site) and thus a different activation entropy. With a broad set of computations and experimental analyses, the level of evidence is considered solid by some reviewers. On the other hand, there remain limitations in the computational analyses, especially regarding free energy profiles using different methodologies (shape of free energy profiles with DFTB vs. PBE QM/MM, and barriers with steered MD and umbrella sampling) and the activation entropy, leading some reviewers to the evaluation that the level of evidence is incomplete.

Reviewed by eLife

Mechanism of dimer selectivity and binding cooperativity of BRAF inhibitors

1. Joseph Clayton
2. Aarion Romany
3. Evangelia Matenoglou
4. Evripidis Gavathiotis
5. Poulikos I Poulikakos
6. Jana Shen

• Curated by eLife

  eLife Assessment

  This fundamental study illuminates the dynamics of BRAF in its monomeric and dimeric forms, both in the absence and presence of inhibitors, through a convincing combination of traditional experiments and sophisticated computational analyses. By revealing novel insights into the selectivity and cooperative processes of BRAF inhibitors, it holds significant promise for the development of future therapeutics, particularly against mutant isoforms in cancer. Overall, these findings will be of great interest to structural biologists, medicinal chemists, and pharmacologists.

Reviewed by eLife

Huntingtin S421 phosphorylation increases kinesin and dynein engagement on early endosomes and lysosomes

1. Emily N.P. Prowse
2. Abdullah R. Chaudhary
3. David Sharon
4. Adam G. Hendricks

Reviewed by preLights