While much of our current understanding in redox biology has been derived using these pioneering methods, some key limitations remain to be addressed.
#Lost rosetta stone activation id free#
In most cases, free thiol ushers regain in enzymatic activity. Many of these ROS adducts involve direct modification of the active-site cysteine residue that is privileged due to its low p K a and low kinetic barrier to reaction with ROS. (13) Deubiquitinating/deSUMOylating enzymes (DUBs/SENPs) are mostly thiol-active proteases many DUBs and SENPs are indeed targets of ROS. These conjugating enzymes are ROS-sensitive. Unlike phosphorylation, ubiquitination is dominated by reactive thiol chemistry: Ub-conjugation proceeds through multiple enzyme-bound Ub-thioester intermediates. (8-11) Because ROS and RES exist at low levels during signaling, sensor residues on redox-responsive proteins are likely “kinetically privileged”, i.e., inherently tuned to rapidly react with specific ROS/RES (12) with rapid second-order rate constants (high k cat/ K m). In this paradigm, reactive oxygen or electrophilic species (ROS/RES) directly modify a specific signal-sensing protein, preempting decision-making.
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This work establishes Ube2V2 as a Rosetta-stone bridging redox and ubiquitin codes to guard genome integrity.Īgainst the backdrop of these exquisite enzyme-regulated signaling subsystems, the cell has also harnessed reactive small-molecule signaling mediators to fine-tune responses. Contrasting conventional active-site/off-active-site cysteine-modifications that regulate target activity, modification of Ube2V2 allosterically hyperactivated its enzymatically active binding-partner Ube2N, promoting K63-linked client ubiquitination and stimulating H2AX-dependent DNA damage response. Thus, G-REX is an unbiased method to identify novel functional cysteines.
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This non-enzyme-catalyzed-PTM triggered responses specific to each protein. G-REX identified two allosteric ubiquitin-conjugating proteins-Ube2V1/Ube2V2-sharing a novel privileged-sensor-cysteine. Mitigating toxicity/off-target effects associated with uncontrolled bolus exposure, G-REX tagged first-responding innate cysteines that bind electrophiles under true k cat/ K m conditions.
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Herein, we designed “G-REX”-a technique that allows controlled release of reactive electrophiles in vivo. Despite the latest impetus toward harnessing kinetically and functionally privileged cysteines for electrophilic drug design, identifying these sensors remains challenging. However, the reemergence of electrophilic drugs has ushered mining of unconventional/non-enzyme-catalyzed electrophile-signaling pathways. Posttranslational modifications (PTMs) are the lingua franca of cellular communication.