The Humble Phosphate Ion: Making Life “Go”

Author: John Charpentier

Editors; Noah Steinfeld, Tricia Garay, and Scott Barolo

A glance into any organic chemistry or biochemistry textbook reveals a dizzying variety of chemical compounds, reactions and mechanisms. It is not at all obvious why one particular class of reaction, the attachment and detachment of a phosphate group (PO43-) to molecules like nucleotides and proteins, is central to making the chemistry of life “go.”

Proteins: Not Just for Getting Swole, Brah

Fig1
Figure 1. A phosphate ion. Note the negative charges.

Proteins are the working-class heroes of the cell: they get things done. A protein’s function is largely determined by its shape, which in turn is dictated by the linear sequence of chemically distinct amino acid subunits it is composed of. The rules of protein folding are astonishingly complex. Generally speaking, the reluctance of hydrophobic (“water-fearing”) amino acids to project outward into the watery cytoplasm is the primary determinant of protein shape, but electrostatic interactions between amino acid residues are also important. Phosphate groups have three negative charges, which means that when they are linked to or removed from a protein by specialized enzymes, they can dramatically modify its shape and stability, and therefore its function. The phosphorylation/dephosphorylation cycle operates like a switch to regulate protein behavior: add a phosphate and you get a violent Mr. Hyde protein; take it off and you get the amiable Dr. Jekyll.

 

Fig2
Figure 2. Cellular homunculi don’t exist – decisions are made by integrating signaling inputs from the environment to effect changes in gene expression.

So where do we find phosphorylation in biochemistry? The answer is: pretty much everywhere! I will discuss two key examples. Firstly, phosphorylation is important in “cell signaling,” the sensing of messages from outside a cell and their incorporation into cellular decision-making. It’s worth observing that there isn’t anything we’d recognize as a brain in cells – decision-making is an emergent property of the integration of these signals, not the doing of a microscopic cellular homunculus pulling levers or “thinking.”

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Training T Cell Assassins

Author: John Charpentier

Editors: Zena Lapp, Theresa Mau, and David Mertz

 

t_cell_assassin
Figure 1. An encounter between a CAR-T cell and a cancer cell

 

The assassins have a description of their targets, who are hiding in plain sight among the non-combatants. The targets are guerillas who’ve infiltrated the neighborhood, overwhelming the local authorities and fomenting chaos. After only minutes on patrol, the assassins go on the attack, quickly identifying and eliminating the enemy without harming a single bystander.

This scenario may sound like the plot of a Hollywood blockbuster, but it’s also a good metaphor to describe the activity of engineered immune cells against cancer cells. The assassins are called CAR-T (Chimeric Antigen Receptor-T) cells, and they receive their elite training at the hands of physicians and scientists, who teach them to recognize particular molecules on the surface of tumors.

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