Biochemical controls: intracellular electrical controls (Introduction)

by David Turell @, Saturday, September 10, 2022, 15:54 (81 days ago) @ David Turell

Using very advanced techniques:

"New findings reported in PNAS by Toyama et al. are uncovering a role for electrostatics in enzymatic activity. Simultaneously, the discovery may offer insight into the function of so-called “disordered proteins” that never fold into stable structures, and other proteins containing disordered regions that would seem to flail about like loose cables. But there is order in the disorder! How big is this discovery?

"Electrostatic interactions play important roles in regulating a plethora of different biochemical processes and in providing stability to biomolecules and their complexes (my bold)

"What the team from the University of Toronto found, discussed below, was only made possible by “solution NMR spectroscopy.” This technique allows them, for the first time, to measure the near-surface electrostatic potentials of individual atoms in proteins and follow changes in those potentials during an enzyme’s action.

"Our results collectively show that a subtle balance between electrostatic repulsion and interchain attractive interactions regulates CAPRIN1 phase separation and provides insight into how nucleotides, such as ATP, can induce formation of and subsequently dissolve protein condensates.

"CAPRIN1 (cell cycle associated protein 1) is an RNA-binding protein “localized to membraneless organelles playing an important role in messenger RNA (mRNA) storage and translation.” It may act as a negative regulator of translation, confining mRNAs in condensates at times to prevent overproduction of proteins. “CAPRIN1 is found in membraneless organelles, such as stress granules, P bodies, and messenger RNA (mRNA) transport granules, where, in concert with a variety of other RNA-binding proteins, it plays an important role in regulating RNA processing,” the paper explains.

"CAPRIN1 contains IDP tails at both ends which, it turns out, are the key to condensate formation. The Toronto team found, importantly, that ATP plays a dynamic role in the electrostatic changes of CAPRIN1, especially in its IDP regions. In brief, here is what happens (see Figure 5 in the paper). Specific amino acid residues in the IDP regions confer on them a net positive charge. This makes the tails repel each other, resisting condensate formation (and preventing self-association of the tails). When ATP attaches to the IDP regions, however, the net charge is reduced, permitting intermolecular interactions. As more ATP is added, the collection becomes neutral, and a condensate forms. Additional ATP inverts the electrical potential, making it negative. Electrostatic repulsion ensues again, causing breakup of the condensate, separating the contents and freeing them up for the next round.

"This implies that condensate formation has an electrical aspect to it. Since it relies on the sequence and position of specific amino acid residues, one might even call it an electric code.


"The information in the sequence of amino acids, and of the codons in the genes that encode them, appears to play critical roles in condensate formation and, simultaneously, in enzymatic behavior. Some amino acids they dub “stickers” promote phase separation. The specific electrostatic attractions and repulsions that give rise to the enzyme’s function during condensate formation and dissolution is dependent on the positions of these stickers.

"This remarkable revelation begins to give insight into the participation of cell coding with electrophysics. Get a charge out of that!

"CAPRIN1 coexists with negatively charged RNA molecules in cells and, along with FMRP and other proteins, is implicated in the regulation of RNA processing and translational activity. Thus, electrostatics play a central role in modulating the biological functions of this protein, and measurement of electrostatic potentials at each site along its backbone, as reported here, provides an opportunity to understand in more detail the important role of charge in this system. (my bold)

"The paper only investigated one enzyme, so caution is advised before generalizing. The authors feel, though, that this electrical code model will help explain many other processes that require molecules to come together, perform their work, and then separate. It’s the new Electric Cell."

Comment: electrostatic controls add another amazing layer to the complexity of the cell. Since all proteins contain charged areas the use of electrostatic charges to control molecular movements makes perfect sense.

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