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Signal sequence-triage is activated by translocon obstruction sensed by an ER stress sensor IRE1α
No full textSecretory pathway proteins are cotranslationally translocated into the endoplasmic reticulum (ER) of metazoan cells through the protein channel, translocon. Given that there are far fewer translocons than ribosomes in a cell, it is essential that secretory protein-translating ribosomes only occupy translocons transiently. Therefore, if translocons are obstructed by ribosomes stalled or slowed in translational elongation, it possibly results in deleterious consequences to cellular function. Hence, we investigated how translocon clogging by stalled ribosomes affects mammalian cells. First, we constructed ER-destined translational arrest proteins (ER-TAP) as an artificial protein that clogged the translocon in the ER membrane. Here, we show that the translocon clogging by ER-TAP expression activates triage of signal sequences (SS) in which secretory pathway proteins harboring highly efficient SS are preferentially translocated into the ER lumen. Interestingly, the translocon obstructed status specifically activates inositol requiring enzyme 1α (IRE1α) but not protein kinase R-like ER kinase (PERK). Given that the IRE1α$2013XBP1 pathway mainly induces the translocon components, our discovery implies that lowered availability of translocon activates IRE1α, which induces translocon itself. This results in rebalance between protein influx into the ER and the cellular translocation capacity.journal articl
Extracting quantitative relationships between cell motility and molecular activities (Analytical approaches and implications)
No full textDespite considerable advancements in biological measurement technologies, capturing the simultaneous temporal changes in various biomolecular concentrations remains a challenge. Overcoming this technical difficulty via data preprocessing could not only clarify the principles of biological functions but also reduce the costs associated with advancing measurement technologies. This review introduces a novel approach to harmonizing heterogeneous time-series data related to molecular signaling and cellular movement. In response to this challenge, we developed and employed a motion-trigger average (MTA) algorithm. The MTA comprehensively screens and averages intracellular molecular activities that coincide with targeted velocity patterns of the moving cell edge. Given that the MTA filters out cell individuality-dependent noise from the data, a straightforward regression equation can correlate edge moving velocities with the molecular activities of various species within the cell. This methodology not only integrates fragmented datasets but also enables the reuse of past data for new analyses. The crux of our discovery is the elucidation of the role that Rho GTPases play in regulating cellular edge dynamics, a finding made possible by adopting the MTA algorithm. Our study suggests that the MTA could become an indispensable tool in data-driven biology, potentially paving the way for considerable insights into dynamic cellular behaviors and the underlying biological principles.journal articl
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Discovering Natural Anti-COVID Agents Based on Combined Sequence and Docking Study
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Multistep conformational changes leading to the gate opening of light-driven sodium pump rhodopsin
No full textMembrane transport proteins require a gating mechanism that opens and closes the substrate transport pathway to carry out unidirectional transport. The "gating" involves large conformational changes and is achieved via multistep reactions. However, these elementary steps have not been clarified for most transporters due to the difficulty of detecting the individual steps. Here, we propose these steps for the gate opening of the bacterial Na+ pump rhodopsin, which outwardly pumps Na+ upon illumination. We herein solved an asymmetric dimer structure of Na+ pump rhodopsin from the bacterium Indibacter alkaliphilus. In one protomer, the Arg108 sidechain is oriented toward the protein center and appears to block a Na+ release pathway to the extracellular (EC) medium. In the other protomer, however, this sidechain swings to the EC side and then opens the release pathway. Assuming that the latter protomer mimics the Na+-releasing intermediate, we examined the mechanism for the swing motion of the Arg108 sidechain. On the EC surface of the first protomer, there is a characteristic cluster consisting of Glu10, Glu159, and Arg242 residues connecting three helices. In contrast, this cluster is disrupted in the second protomer. Our experimental results suggested that this disruption is a key process. The cluster disruption induces the outward movement of the Glu159-Arg242 pair and simultaneously rotates the seventh transmembrane helix. This rotation resultantly opens a space for the swing motion of the Arg108 sidechain. Thus, cluster disruption might occur during the photoreaction and then trigger sequential conformation changes leading to the gate-open state.journal articl
Task-relevant Model-based Reinforcement Learning for Contact-rich Robotic Tasks
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Stromal cell-derived factors that control gastric stem cells
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Polyhomeotic homolog 1 (Phc1) confers a permissive effect during neural differentiation through epigenetic regulation
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Microfluidic device for high-throughput and high-sensitive flow cytometry toward cell and droplet analysis
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