Biophysics

Kinetic regulation of kinesin’s two motor domains coordinates its stepping along microtubules

1. Yamato Niitani
2. Kohei Matsuzaki
3. Erik Jonsson
4. Ronald D Vale
5. Michio Tomishige

• Curated by eLife

  eLife Assessment

  This study provides compelling evidence that kinesin's stepping mechanism is governed by strain-induced conformational changes in its nucleotide-binding pockets. Using pre-steady state kinetics and single-molecule assays, the authors demonstrate that the neck linker's conformation differentially modulates nucleotide affinity and detachment rates, establishing an asynchronous chemo-mechanical cycle that prevents simultaneous detachment. Supported by cryo-EM structural data, the work presents an important advance in our understanding of kinesin's hand-over-hand movement.

  [Editors' note: this paper was reviewed by Review Commons.]

Reviewed by eLife, Review Commons

Load-based divergence in the dynamic allostery of two TCRs recognizing the same pMHC

1. Ana Cristina Chang-Gonzalez
2. Aoi Akitsu
3. Robert J Mallis
4. Matthew J Lang
5. Ellis L Reinherz
6. Wonmuk Hwang

• Curated by eLife

  eLife Assessment

  This useful study reports detailed molecular dynamics (MD) simulations of T-cell receptors (TCRs) in complex with a peptide/MHC complex, for a better understanding of the mechanism of T-cell activation. The MD simulations provide solid evidence supporting that different TCRs can respond mechanically in different ways upon binding to the same pMHC complex. The analyses are systematic and provide testable predictions that can be evaluated by future mutagenesis and force microscopy studies.

Reviewed by eLife

Deletion of PIEZO1 in adult cardiomyocytes accelerates cardiac aging and causes premature death

1. Ze-Yan Yu
2. Yang Guo
3. Scott Kesteven
4. Delfine Cheng
5. Hanzhou Lei
6. Jianxin Wu
7. Evelyn Nadar
8. Peter Macdonald
9. Munira Xaymardan
10. Charles D. Cox
11. Michael P. Feneley
12. Boris Martinac

Reviewed by preLights

A role for JAK2 in mediating cell surface GHR-PRLR interaction

1. Chen Chen
2. Jing Jiang
3. Tejeshwar C Rao
4. Ying Liu
5. Tatiana T Marquez Lago
6. Stuart J Frank
7. André Leier

• Curated by eLife

  eLife Assessment

  This is an important study that characterizes a surprising interaction between two different cytokine/hormone receptors using nanoscale resolution (dSTORM) microscopy. The study provides solid evidence that the interaction is ligand-dependent, and is mediated by the receptor-associated intracellular signalling molecule JAK2. While at present limited to growth hormone and prolactin receptors in a limited number of cell lines, there are potentially broad implications for cytokine signalling, as such JAK2-mediated interactions could occur between a range of different cytokines. Moreover, the specific hormone interactions shown in the manuscript may have significant implications for understanding how these hormones can have differential effects in breast cancer, under different conditions.

Reviewed by eLife

Distinct activation mechanisms of CXCR4 and ACKR3 revealed by single-molecule analysis of their conformational landscapes

1. Christopher T Schafer
2. Raymond F Pauszek
3. Martin Gustavsson
4. Tracy M Handel
5. David P Millar

• Curated by eLife

  eLife Assessment

  This manuscript describes the characterization of the conformational dynamics of two chemokine receptors at the single-molecule level using FRET. The authors make a convincing case for attributing the distinct interaction and pharmacology of the two receptors to differences in their conformational energy landscape. These important findings will be of interest to scientists working on activation mechanisms of GPCRs and signal transduction.

Reviewed by eLife

Elucidating the Mechanism Underlying UBA7•UBE2L6 Disulfide Complex Formation

1. Pei-Tzu Chen
2. Jia-Yin Yeh
3. Jui-Hsia Weng
4. Kuen-Phon Wu

• Curated by eLife

  eLife Assessment

  In this important study, the authors employed state-of-the-art biochemistry, cryo-EM, and HDX mass spec approaches to study the formation of the binary Uba7-UBE2L6 and ternary UBA7-UBE2L6-ISG15 complexes. The results established mechanisms by which UBA7 and UBE2L6 form disulfide bonds, disrupting the ISG15 transfer cascade. While the biochemical and structural experiments are largely convincing, the mechanism under in vivo conditions remains unclear, due to the limited use of a single E2 enzyme. The authors need to repeat their experiments with a representative panel of human E2 enzymes.

Reviewed by eLife

Progressive chromosome shape changes quantified during cell divisions

1. Yasutaka Kakui
2. Yoshiharu Kusano
3. Tereza Clarence
4. Maya Lopez
5. Toru Hirota
6. Bhavin S. Khatri
7. Frank Uhlmann

Reviewed by Review Commons

A differentiable Gillespie algorithm for simulating chemical kinetics, parameter estimation, and designing synthetic biological circuits

1. Krishna Rijal
2. Pankaj Mehta

• Curated by eLife

  eLife Assessment

  This important study introduces a fully differentiable variant of the Gillespie algorithm as an approximate stochastic simulation scheme for complex chemical reaction networks, allowing kinetic parameters to be inferred from empirical measurements of network outputs using gradient descent. The concept and algorithm design are convincing and innovative. While the proofs of concept are promising, some questions are left open about implications for more complex systems that cannot be addressed by existing methods. This work has the potential to be of significant interest to a broad audience of quantitative and synthetic biologists.

Reviewed by eLife

Structure and Cl- Conductance Properties of the Open State of Human CFTR

1. Zhi-Wei Zeng
2. Christopher E Ing
3. Régis Pomès

• Curated by eLife

  eLife Assessment

  This important study reports a detailed computational analysis of the CFTR ion channel's permeation mechanism, advancing our understanding of its structure-function relationship. The conclusions are based on extensive molecular dynamics simulations and thorough analysis, but the use of an approximate chloride ion model, known to underestimate key ion-protein interactions, leaves them incomplete without experimental or alternative computational validation. The work will be of interest to biophysicists working on CFTR and cystic fibrosis.

Reviewed by eLife

A thermodynamic framework for nonequilibrium self-assembly and force morphology tradeoffs in branched actin networks

1. Elisabeth Rennert
2. Suriyanarayanan Vaikuntanathan

• Curated by eLife

  eLife Assessment

  Rennert et al. developed a valuable thermodynamic framework to study the force response of branched actin networks from the crucial and unexplored perspective of energetic cost. They used the fact that the entropy production rate must be positive to derive inequalities that set limits on the maximum force produced by branched actin networks, and speculate that the dissipative cost beyond that required to move the load may be necessary to maintain an adaptive steady state. This work is highly innovative, but remains incomplete until the hypotheses of the model are better justified and the conclusions about the dissipative cost of the system are better established.

Reviewed by eLife