Biophysics

DNAJA2 and Hero11 mediate similar conformational extension and aggregation suppression of TDP-43

1. Andy Y.W. Lam
2. Kotaro Tsuboyama
3. Hisashi Tadakuma
4. Yukihide Tomari

Reviewed by Review Commons

Gating interactions steer loop conformational changes in the active site of the L1 metallo-β-lactamase

1. Zhuoran Zhao
2. Xiayu Shen
3. Shuang Chen
4. Jing Gu
5. Haun Wang
6. Maria F Mojica
7. Moumita Samanta
8. Debsindhu Bhowmik
9. Alejandro J Vila
10. Robert A Bonomo
11. Shozeb Haider

• Curated by eLife

  eLife assessment

  In this useful study, the authors utilize state-of-the-art computational methods complemented with some experimental validation to investigate the dynamics of flexible loops of the L1 Metallo-β-lactamase enzyme, resulting in a better understanding of the various conformational states useful for the rational design of superior β-lactamase inhibitors/antibiotics. The evidence supporting the claims is solid, and the work will be of interest to computational, experimental biologists, and drug designers working on antibiotic resistance.

Reviewed by eLife

The SARS-CoV-2 accessory protein Orf3a is not an ion channel, but does interact with trafficking proteins

1. Alexandria N Miller
2. Patrick R Houlihan
3. Ella Matamala
4. Deny Cabezas-Bratesco
5. Gi Young Lee
6. Ben Cristofori-Armstrong
7. Tanya L Dilan
8. Silvia Sanchez-Martinez
9. Doreen Matthies
10. Rui Yan
11. Zhiheng Yu
12. Dejian Ren
13. Sebastian E Brauchi
14. David E Clapham

• Curated by eLife

  eLife assessment

  The function of specific proteins made by SARS-CoV-1 and SARS-CoV-2 is under debate, with diverging claims previously published regarding the ability of Orf3a proteins from either virus to form ion channels. The authors undertook a thorough characterization of Orf3a from CoV-1 and CoV-2 by combining data from a range of different structural and functional experiments, arguably providing the most compelling evidence to date that Orf3a from viruses is not an ion channel. Instead, the orthologue-specific interaction with a component of a larger protein complex suggests a role of one of the two membrane proteins in the endo-lysosomal pathway. The work is significant from a fundamental science perspective, for its implications for COVID antiviral development strategies, and also for establishing guidelines for future identification of true viral ion channels.

Reviewed by eLife

Drug specificity and affinity are encoded in the probability of cryptic pocket opening in myosin motor domains

1. Artur Meller
2. Jeffrey M Lotthammer
3. Louis G Smith
4. Borna Novak
5. Lindsey A Lee
6. Catherine C Kuhn
7. Lina Greenberg
8. Leslie A Leinwand
9. Michael J Greenberg
10. Gregory R Bowman

• Curated by eLife

  eLife assessment

  This important study presents insights into how conformational dynamics differentially influences drug specificity and affinity in myosin isoforms using computational approaches. The evidence supporting the conclusions is convincing, establishing a relationship between inhibition and protein dynamics using state of the art computational techniques followed by experimental validation. The work will be of broad interest to computational biophysicists and medicinal chemists.

Reviewed by eLife

Dynamics of immune memory and learning in bacterial communities

1. Madeleine Bonsma-Fisher
2. Sidhartha Goyal

• Curated by eLife

  eLife assessment

  In this important work, the authors develop a theory for the co-evolutionary dynamics of bacteria and phages, where the major evolutionary pressure comes from CRISPR-Cas adaptive immunity in bacteria. Through extensive stochastic numerical simulations and analytical calculations, the paper presents a compelling analysis of the emergent properties of immune interactions, in the regime of a single proto-spacer and a single spacer. Some of the trends highlighted by the model are recovered from experimental data. The main results concern how diversity in both phage and bacteria population are linked and are shaped by immunity, and should be of broad interest in immunology.

Reviewed by eLife

Mechanical basis and topological routes to cell elimination

1. Siavash Monfared
2. Guruswami Ravichandran
3. José Andrade
4. Amin Doostmohammadi

• Curated by eLife

  eLife assessment

  In this work, Monfared et al. construct a useful three-dimensional phase-field model for cell layers and use this to investigate the link of extrusion events to defects in cellular arrangement. The extension of existing 2D phase field models to three dimensions is an important contribution of this paper. Here the model is used to study the importance of cell-cell and cell-substrate interaction in extrusion from cell monolayers. Their claim that extrusion events can be distinctly linked to defects in nematic and hexatic orders in the monolayer need to be better justified to be fully convincing.

Reviewed by eLife

Conformational and oligomeric states of SPOP from small-angle X-ray scattering and molecular dynamics simulations

1. F Emil Thomasen
2. Matthew J Cuneo
3. Tanja Mittag
4. Kresten Lindorff-Larsen

• Curated by eLife

  eLife assessment

  In this important paper, the authors have developed an approach for simultaneously optimizing the conformational ensemble and degrees of oligomerization, and this has been tested by applying it to a specific protein (SPOP). Comparison of the quality of fits with different models also provides valuable insights into structural features important to the assembly of oligomers. The approach, presented with compelling experimental support, is potentially applicable to other systems as well.

Reviewed by eLife

Tracking multiple conformations occurring on angstrom-and-millisecond scales in single amino-acid-transporter molecules

1. Yufeng Zhou
2. John H Lewis
3. Zhe Lu

• Curated by eLife

  eLife assessment

  This paper presents a single-molecule polarization microscopy study aimed at monitoring the arginine/agmatine antiporter AdiC as it transiently exchanges between conformational states. This approach measures how a bis-TMR fluorophore anchored onto helix 6a changes its orientation in the microscope, and the authors identify four states that they propose correspond to the key steps in the transport cycle (inward-open, inward occluded, outward occluded and outward open). This is a cutting-edge and challenging approach that sets the stage for direct measurements of conformational equilibria and will thus be of interest to anyone studying transport mechanisms. However, additional investigation is required to validate the robustness of the post-processing of the single-molecule data to yield the four-state model compared to alternate models, to test the robustness of the data with transport mutants/conditions that would slow or eliminate states, and to consolidate transitions that are observed that conflict with previous observations of obligatory coupling in AdiC.

Reviewed by eLife

State-specific morphological deformations of the lipid bilayer explain mechanosensitive gating of MscS ion channels

1. Yein Christina Park
2. Bharat Reddy
3. Navid Bavi
4. Eduardo Perozo
5. José D Faraldo-Gómez

• Curated by eLife

  eLife assessment

  The manuscript reports a new structure of the small conductance mechanosensitive channel MscS from E. coli in the open state, together with coarse-grained and atomistic molecular dynamics simulations of MscS and the related channel MSL1 of plant mitochondria in closed and open states. The important finding is that the surrounding lipid bilayer is severely distorted in the closed state only, with the protein inducing high curvature in the inner leaflet due to the membrane protruding into the cytoplasm. The authors argue convincingly that the role of membrane tension is to increase the energy of the protein-membrane system in this closed state compared to the relatively flat-membrane open state, in contrast to the previous proposal that tension-induced gating is driven by expansion of the in-plane area of the protein. The finding may be relevant for the understanding of ion channel mechano-sensation more generally, including of the PIEZO1 channel.

Reviewed by eLife

Evolutionary divergence in the conformational landscapes of tyrosine vs serine/threonine kinases

1. Joan Gizzio
2. Abhishek Thakur
3. Allan Haldane
4. Ronald M Levy

• Curated by eLife

  eLife assessment

  This important paper provides a convincing mechanism for relative binding specificity of Type II inhibitors to kinases. The combination of a sequence-derived Potts-model with experimental dissociation constants and calculated free energies of binding to the DFG-out state is highly compelling and goes beyond the current state of the art. Given the importance of kinases in pathophysiological processes, the results will be of interest to a broad audience and, in addition, the combination of computational methods can be applicable to a wide variety of other biophysical processes that involve conformational rearrangements.

Reviewed by eLife