Biological complexity: phase separation (Introduction)

by David Turell , Sunday, November 06, 2022, 16:40 (748 days ago) @ David Turell

Reaction areas without actual physical wall separation:

https://knowablemagazine.org/article/living-world/2020/what-is-liquid-liquid-phase-sepa...

"... a big question mark remains: How do the right proteins organize themselves in a sea of fluid swarming with millions of molecules? Do they bump into each other by chance, or does the cell actively organize its fluid space to bring the correct partners together?

" Over the last decade, cell biologists have come to appreciate what many believe to be a whole new way that cells shape their internal landscape. Like blobs merging, then dispersing, in a lava lamp, or a salad dressing that separates into bubbles of oil and vinegar, groups of proteins can sometimes congeal into distinct droplets. One key way these droplets form is through a process called liquid-liquid phase separation.

"Exactly what happens within these droplets largely remains a mystery. The blobs might act as temporary breakout spaces for specific cellular events, for example. Or their formation might result from a stage in some key cellular process. But whatever their precise functions turn out to be, some biologists think that their formation promises to fundamentally reframe our understanding of how the cell does its essential business.

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"To understand the concept, it helps to understand the properties of the cell’s interior, or cytoplasm. Researchers call it a fluid, but it’s more oozy than watery, like cornstarch mixed with a bit of water. That’s because it’s chock-full of dissolved molecules, explains Stephanie Weber, a cell biologist at McGill University in Montreal. When clusters of those molecules begin to separate out, they create even gooier, molasses-like pockets of cytoplasm called biomolecular condensates.

"Structurally, the proteins within a condensate are a bit like a tangle of cooked spaghetti, if you can imagine spaghetti strands made of weak Velcro. They bind lightly to many parts of the other proteins in the condensate, in no particular orientation. (Contrast that with the key-in-a-lock kind of binding that occurs when an enzyme attaches to a target or a chemical sticks to a receptor.) Many of the proteins or protein regions that make these weak connections are what biochemists call disordered, meaning they don’t take on a firm three-dimensional shape like most proteins do. The sum of all those weak forces holds the droplet together.

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"The biggest, broadest hypothesis for the function of these droplets is that they concentrate specific sets of proteins and other molecules so as to house, kick-start or speed up the reactions the proteins engage in.

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"The phase separation may rev up a molecular process that normally ticks over barely above idle, the researchers proposed.

"And work from geneticist Richard Young’s lab at the Massachusetts Institute of Technology suggests that phase separation concentrates droplets of proteins needed to turn on the activity of genes or prod a chromosome to start copying itself at the correct places on the DNA strand. Rather than relying on chance for the right proteins to appear where they are needed, the droplets form what Young calls “a goody bag” of all the components that are necessary for these processes to occur.

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"Until recently, Drummond worried that the idea of condensates as compartments was distracting researchers from thinking more broadly about what these structureless structures might be doing, though recently their focus has expanded. “There are many alternatives to the simplistic notion that this is all about encapsulating some biochemical reaction,” he says. For example, droplets might keep enzymes or other molecules out of the general cytoplasm so that they don’t undergo certain reactions, releasing them only when the cell needs them or when a process they might interrupt is completed.

"Much of the evidence for this and other functions of phase separation is circumstantial so far, because direct proof is tough to get. Researchers generally test how cellular processes work by perturbing them, but it’s hard to disrupt phase separation without also breaking up protein interactions that are closely associated with it, making it challenging to draw conclusions about cause and effect.

"Or, as Drummond’s own work suggests, some proteins may phase-separate in response to an environmental cue, such as temperature. In that scenario, a cell’s ability to detect the change might serve as a finely tuned sensor.

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"Mittag and others agree that they have barely scratched the surface of how this new field might transform cell biology. “I think there’s no doubt that phase separation plays a very important role for cells,” she says. Researchers so far have identified at least 20 different types of phase-separated droplets, each consisting of different proteins and other molecules and emerging under different circumstances.

"Some condensates, like P granules, are long-standing characters in the cell, newly identified as products of phase separation. Others are just emerging. The diversity is not surprising, says Lee: Just like cell organelles that are bounded by membranes all have different functions, membraneless ones probably do too."

Comment: physical chemistry has come to biology, and it is not an easy fit.