The ubiquitin wars

Ubiquitin used to be simple.  All it had to do was form an amide between its carboxy terminal glycine and the epsilon amino group of lysine of a target protein, and bingo — the protein was targeted for degradation by the proteasome.

Before proceeding, it’s worth thinking why this sort of thing doesn’t happen more often, by which I mean amide formation between carboxyl groups on aspartic and glutamic acid on one protein and lysines on the surface of another.  That’s where the 3 amino acids are likely to be found, because they are charged at physiological pH, meaning they cost energy (and probably entropy) to put into the relatively hydrophobic interior of a protein where there isn’t a lot of water around to hide their charges.   Also, every noncyclic protein (which is just about all of them) has a carboxy terminal amino acid — why don’t they link up spontaneously to the lysines on the surface of other proteins?

Well, ubiquitin does NOT link up spontaneously.  It has a suite of enzymes to do so.  Like a double play in baseball, 3 enzymes are involved, which move ubiquitin to E1 (the shortstop) to E2 (the second baseman) to E3 (the first baseman).  We have over 600 E3 enzymes, 40 E2s and 9 E1s.  650/20,000 protein coding genes is a significant number — and the 600 E3s are likely there to provide specificity to just what protein gets linked to.

Addendum 21 Feb — Silly me, I should have added in the nearly 100 genes coding for proteins that remove attached ubiquitins (e.g. the deubiquitinases).

A few more fun facts and then down to business.  First ubiquitin is so stable that boiling water doesn’t denature it [ Science vol. 365 pp. 502 – 505 ’19 ].  Second ubiquitin can link to itself, as it contains 7 lysines at amino acids 6, 11, 27, 28, 33, 48 and 63 of the 72 amino acids contained in the protein.

Polyubiquitin chains are often made up of multiple ubiquitin monomers with lengths up to 10 [ Nature. vol. 462 pp. 615 – 619 ’09  2009 ] meaning that there could be a lot of different ones ( 7^10 = 282,475,249.  However chains found in nature seem to use just one type of link, e.g. linking the carboxyl group of one ubiquitin to just one of the 7 lysines over and over, forming a rather monotonous polymer.

On to the interesting paper, namely the ubiquitin wars inside a macrophage invaded by TB [ Nature vol. 577 pp. 682 – 688 ’20 ]  Ubiquitin initially was thought to be a tag marking a protein for destruction.  It’s much more complicated than that.  A host E3 ubiquitin ligase (ANAPC2, a core subunit of the anaphase promoting complex/cyclosome) promotes the attachment of lysine #11 linked ubiquitin chains to lysine #76 of the TB protein Rv0222.  In some way this helps Rv022 to suppress the expression of proinflammatory cytokines.

We do know that the ubiquitination of Rv022 facilitates in some way the recruitment of the protein tyrosine phosphatase SHP1 to the adaptor protein TRAF6 (Tumor necrosis factor Receptor Associated Family member 6) preventing the its ubiquitination and activation.  Of interest is the fact that TRAF6 itself is an E3 ubiquitin ligase which acts on many proteins.

Now to continue and show the further complexity of what’s going on inside our cells.  Autophosphorylated IRAK leaves the TLR (Toll Like Receptor) signaling complex forming a complex with TRAF6 resulting in the oligomerization of TRAF6.  Somehow this activates TAK1, a member of the MAP3 kinase family and this leads to the activation of the family of IKappaB kinases which phosphorylate IKappaB leading to its proteolysis.  Once IKappaB is removed from NFKappaB, translation of NFKappaB to the nucleus occurs where it turns on transcription of cytokines and other proinflammatory genes.

It is really amazing when you think of all the checks and balances going on down there.  How crude our weapons against inflammation are now, compared to what we might have when we know all the mechanisms behind it.

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  • Ben L  On February 22, 2020 at 4:12 pm

    Somewhat unrelated to this post, but I’d like to get more out of these, so do you (or other readers of this blog!) have any book (or several) recommendations for chemistry? Picking up mostly where high school left off.

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