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Liquid Drops of Protein Inside Cells

There’s a set of recent papers that tell us that there’s a lot that we don’t know about how proteins behave inside cells. And that there’s a lot that we don’t know about cell biology, either. So-called “membraneless organelles” are common and important, but how they’re formed and why they exist that way have been unanswered questions. It now appears that some of these exist because many types of proteins can (either on their own or by associating with RNA) form liquid-like drops, a phase change that is reversible under various conditions.

Well, we already knew that proteins had complicated structural behavior, to put it mildly, and that parts of them (and some entire proteins) are intrinsically disordered. It now seems that some intrinsically disordered protein “tails” are involved in this behavior, as well as some prion-type sequences and some poly-Q (arginine glutamine) segments, all of which are found across the proteome (and in the latter cases are known to have both good and bad behavior). Here’s part of a commentary in Science:

Steve McKnight, a bio chemist at the University of Texas Southwestern Medical Center (UTSW) in Dallas, agrees that the field is on the cusp of something profound. “We are seeing the first glimpses of … a whole new understanding of how cells are organized.”

The new work addresses a biological puzzle. Gene expression, and thus most of biology, depends on two large families of proteins: transcription factors, which turn on genes, and RNA-binding proteins (RBPs), which transport RNA to the correct parts of the cell so that they’re in the right place at the right time to be translated into proteins. “The crown jewels of biology,” McKnight calls these families. Oddly, many of these proteins have tails that resemble the self-propagating infectious particles called prions, which cause mad cow disease and, in humans, Creutzfeldt-Jakob disease. But why? “It’s been an enigma,” McKnight says.

The new papers provide an answer, at least for RBPs: The prionlike domains drive the assembly of RBPs into the droplets. . .

And these droplets appear to be a mechanism for the protein/RNA complexes to be packaged and delivered, without having to be surrounded by a membrane of their own (as in a vesicle) and without just being dispersed out into the cytoplasm on their own. It’s a way of sending a concentrated burst of protein and RNA together, and it’s a mechanism that a couple of years ago no one seems to have realized even existed. If you’d asked me last month about liquified drops of protein floating around in the cytoplasm, I’d have given you a funny look, for sure.

Here are a couple of papers from Molecular Cell on all this (and a commentary in that journal as well). Everyone thinking about transcription factors is going to have to take all this on board, and there are probably applications to many other processes as well. It’s always exhilarating (and a bit unnerving) to find out how much important stuff there is that we’ve been totally ignorant of!

8 comments on “Liquid Drops of Protein Inside Cells”

  1. Sam Adams the Dog says:

    These sound like micelles. (?)

  2. Bryan says:

    McKnight had a very neat set of papers in 2012 showing that by using these principles, he could reconstitute hydrogels resembling RNA granules in vitro (doi:10.1016/j.cell.2012.04.016, doi:10.1016/j.cell.2012.04.017). His colleague Michael Rosen had a paper around the same time showing that the same phase-separation behavior occurs with actin-regulatory proteins (doi:10.1038/nature10879), and is a general property of multivalent receptors interacting with multivalent ligands. Given the multivalency of the genome (e.g. it contains regions tiled with nucleosomes containing similar sets of histone modifications), it seems likely that these principles could also underlie the spatial organization of the genome. I’m definitely excited to see more developments coming from this line of research.

  3. Tim says:

    Q is Glutamine (Qute-amine), R is Arginine

  4. matt says:

    Is “droplet” the most apt description? I’m having trouble imagining a droplet in an aqueus solution. Is it just aggregation? Or is aggregation always assumed to be driven by lipophilicity?

  5. Morten G says:

    This has been happening for decades in protein crystallography. It is considered an encouraging sign and worth optimizing (unless of course you have crystals in other conditions). You can even use these oils to seed crystal formation in other conditions.

  6. Sam Adams the Dog says:

    @matt That’s why I suggested micelles….

  7. Bill says:

    Micelles is not far off the mark I think, but maybe this is more about phase behaviour, just like oil and water exist in two liquid phases, it has also long been known that proteins can also do this. under the correct solution conditions, a protein solution will separate into a concentrated protein phase, and a dilute one, but both phases are liquid. This minor phase (the one with the least volume) will form droplets. If a protein has some amphiphilic character (different parts of it want to be in different phases) then it can stabilise the droplets so they don’t coalesce and separate fully. This is all fairly well known.

    I’m guessing what is new here is the idea that the cell uses this behaviour as a mechanism to manipulate and transport proteins?

  8. Me says:

    Colloids?

    My analytical is pretty weak as a small molecule guy – only know about the stuff we use at that level.
    So anybody know what is being imaged here, what system the imaging is taking place in, what technique being used etc?
    This all sounds great but only as good as the work underpinning it.
    And in my head it sounds desperately difficult to actually get a real-life image of what is going on in cells.

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