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1. Correction: The role of energy cost on accuracy, sensitivity, specificity, speed and adaptation of T cell foreign and self recognition

   https://doi.org/10.1039/d1cp90136b  

   Shin, Gyubaek; Wang, Jin (July 2021, Physical Chemistry Chemical Physics)

   null (Ed.)

   Correction for ‘The role of energy cost on accuracy, sensitivity, specificity, speed and adaptation of T cell foreign and self recognition’ by Gyubaek Shin et al. , Phys. Chem. Chem. Phys. , 2021, 23 , 2860–2872, DOI: 10.1039/D0CP02422H. 

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2. Dephosphorylation accelerates the dissociation of ZAP70 from the T cell receptor

   https://doi.org/10.1073/pnas.2116815119  

   Goyette, Jesse; Depoil, David; Yang, Zhengmin; Isaacson, Samuel A.; Allard, Jun; van der Merwe, P. Anton; Gaus, Katharina; Dustin, Michael L.; Dushek, Omer (March 2022, Proceedings of the National Academy of Sciences)

   Protein–protein binding domains are critical in signaling networks. Src homology 2 (SH2) domains are binding domains that interact with sequences containing phosphorylated tyrosines. A subset of SH2 domain–containing proteins has tandem domains, which are thought to enhance binding affinity and specificity. However, a trade-off exists between long-lived binding and the ability to rapidly reverse signaling, which is a critical requirement of noise-filtering mechanisms such as kinetic proofreading. Here, we use modeling to show that the unbinding rate of tandem, but not single, SH2 domains can be accelerated by phosphatases. Using surface plasmon resonance, we show that the phosphatase CD45 can accelerate the unbinding rate of zeta chain–associated protein kinase 70 (ZAP70), a tandem SH2 domain–containing kinase, from biphosphorylated peptides from the T cell receptor (TCR). An important functional prediction of accelerated unbinding is that the intracellular ZAP70–TCR half-life in T cells will not be fixed but rather, dependent on the extracellular TCR–antigen half-life, and we show that this is the case in both cell lines and primary T cells. The work highlights that tandem SH2 domains can break the trade-off between signal fidelity (requiring long half-life) and signal reversibility (requiring short half-life), which is a key requirement for T cell antigen discrimination mediated by kinetic proofreading. 

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3. Modulation of antigen discrimination by duration of immune contacts in a kinetic proofreading model of T cell activation with extreme statistics

   https://doi.org/10.1371/journal.pcbi.1011216  

   Morgan, Jonathan; Lindsay, Alan E. (August 2023, PLOS Computational Biology)

   Lavrik, Inna (Ed.)

   T cells form transient cell-to-cell contacts with antigen presenting cells (APCs) to facilitate surface interrogation by membrane bound T cell receptors (TCRs). Upon recognition of molecular signatures (antigen) of pathogen, T cells may initiate an adaptive immune response. The duration of the T cell/APC contact is observed to vary widely, yet it is unclear what constructive role, if any, such variations might play in immune signaling. Modeling efforts describing antigen discrimination often focus on steady-state approximations and do not account for the transient nature of cellular contacts. Within the framework of a kinetic proofreading (KP) mechanism, we develop a stochasticFirst Receptor Activation Model(FRAM) describing the likelihood that a productive immune signal is produced before the expiry of the contact. Through the use of extreme statistics, we characterize the probability that the first TCR triggering is induced by a rare agonist antigen and not by that of an abundant self-antigen. We show that defining positive immune outcomes as resilience to extreme statistics and sensitivity to rare events mitigates classic tradeoffs associated with KP. By choosing a sufficient number of KP steps, our model is able to yield single agonist sensitivity whilst remaining non-reactive to large populations of self antigen, even when self and agonist antigen are similar in dissociation rate to the TCR but differ largely in expression. Additionally, our model achieves high levels of accuracy even when agonist positive APCs encounters are rare. Finally, we discuss potential biological costs associated with high classification accuracy, particularly in challenging T cell environments. 

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4. Direct Numerical Simulation of Sediment Transport in Turbulent Open Channel Flow Using the Lattice Boltzmann Method

   https://doi.org/10.3390/fluids6060217  

   Hu, Liangquan; Dong, Zhiqiang; Peng, Cheng; Wang, Lian-Ping (June 2021, Fluids)

   The lattice Boltzmann method is employed to conduct direct numerical simulations of turbulent open channel flows with the presence of finite-size spherical sediment particles. The uniform particles have a diameter of approximately 18 wall units and a density of ρp=2.65ρf, where ρp and ρf are the particle and fluid densities, respectively. Three low particle volume fractions ϕ=0.11%, 0.22%, and 0.44% are used to investigate the particle-turbulence interactions. Simulation results indicate that particles are found to result in a more isotropic distribution of fluid turbulent kinetic energy (TKE) among different velocity components, and a more homogeneous distribution of the fluid TKE in the wall-normal direction. Particles tend to accumulate in the near-wall region due to the settling effect and they preferentially reside in low-speed streaks. The vertical particle volume fraction profiles are self-similar when normalized by the total particle volume fractions. Moreover, several typical transport modes of the sediment particles, such as resuspension, saltation, and rolling, are captured by tracking the trajectories of particles. Finally, the vertical profiles of particle concentration are shown to be consistent with a kinetic model. 

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5. Diffusion of a disordered protein on its folded ligand

   https://doi.org/10.1073/pnas.2106690118  

   Wiggers, Felix; Wohl, Samuel; Dubovetskyi, Artem; Rosenblum, Gabriel; Zheng, Wenwei; Hofmann, Hagen (September 2021, Proceedings of the National Academy of Sciences)

   Intrinsically disordered proteins often form dynamic complexes with their ligands. Yet, the speed and amplitude of these motions are hidden in classical binding kinetics. Here, we directly measure the dynamics in an exceptionally mobile, high-affinity complex. We show that the disordered tail of the cell adhesion protein E-cadherin dynamically samples a large surface area of the protooncogene β-catenin. Single-molecule experiments and molecular simulations resolve these motions with high resolution in space and time. Contacts break and form within hundreds of microseconds without a dissociation of the complex. The energy landscape of this complex is rugged with many small barriers (3 to 4 k B T ) and reconciles specificity, high affinity, and extreme disorder. A few persistent contacts provide specificity, whereas unspecific interactions boost affinity. 

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