Monday, August 1, 2016

Another use for TAILS proteomics -- protein fate studies in Pancreatic cancer!!

Check out this paper in Cell. I honestly didn't know this was possible. Partially cause I keep forgetting what the heck TAILS is -- and partially cause this is brilliant.

What is it? An analysis of protein fate. We know tons about how we make proteins through that whole central dogma stuff. DNA --> RNA --> Protein. After that the protein does whatever the protein does, but we've got to get rid of it when it is used up or gets faulty or whatever. Lots of the simulations show that it is naive to consider that a cell has a constant population of complete protein around -- its all somewhere between made -- and being un-made.

This is where the title of the paper just hung me up.  "TAILS shows that protein degradation dominates over proteolytic processing..."???? What the heck does that mean!?!?

Wikipedia helps clear up the title!  We're talking about 2 different mechanisms for getting rid of the old proteins!  Proteolytic processing implies that something like a caspase is finding SPECIFIC proteins and protein sites and destroying the proteins in a systematic and planned fashion.

Protein degradation? That implies its a whole lot less controlled. In cellular systems....I'm going to think that more control = better!

This is where TAILS comes in (also stolen from the WikiPedia did we work without this resource again? Walk to libraries? Dewey Decimals?

In TAILS you start tagging at the protein level!  So if you have two systems...say one that is as scarily under understood as Pancreatic cancer vs normal cell lines, if you see a massive drop in the cancer cell lines in the normal N-termini of your protein, this could be 1) Less overall protein or 2) Less complete proteins!  Cool, right?!?

The tricky part is that you're gonna want to verify that your protein abundances aren't generally shifting, but you can do that with regular old TMT/iTRAQ. And they do.

And to get the conclusions for this paper you're going to need to properly understand your "normal" protein degradation pathways -- what proteins that they cleave AND where. And they do.

So they're able to conclude that a big problem in their pancreatic cancer cell models is that the proteins are being broken down a whole lot more by the generic degradation stuff than the normal controls. Which....might leave one to wonder what is messed up up-stream since caspases are  tightly regulated by all sorts of things...including post-translational modifications (cool paper on that here).

Obviously this is something that requires further and deeper investigation!

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