Blowing up your brain with ubiquitin

I just came back from a Wade Harper talk where we were subjected to an obscene amount of ubiquitin biology and even more ubiquitin nomenclature. This blasting of your brain with technical terms is becoming more and more common with big Biology talks.

But to be honest Prof Harper gave a good talk about an RNAi screen to identify new cell cycle regulators. He's a pretty smart guy (although he needs to take a little more caffeine). A major focus of the talk was on the modulation of Ubiquitination by E3s.

Ubiquitin as you know, is that small peptide that gets conjugated to proteins that are targetted for degradation. But did you know that there are at least eight other ubiquitin related molecules. To date (I believe) only two ubiquitin like molecules have been shown to be covalently linked to other proteins, Nedd8 and SUMO. The process of attaching a ubiquitin is called ubiquitination. Likewise attaching SUMO is Sumolation, and attaching Nedd8 is Neddilation. Still following?

And forget about the process of attaching Ubiquitin it'll hurt (although any biomedical scientist should know this like the back of their hand - although like Perry Farrel said it's more "like slapping yourself in the face")

Still want to hear it? Ubiquitin is first linked to an E1 that transfers the ubiquitin to an E2, then an E3 transfers the ubiquitin from an E2 to a substrate. Some have even brought up the subject of E4s. Now in the human genome there are some E1s, many E2s and a gadzillion E3s. One familly of E3s are called Cullins (discovered by Harper, I think) and this family of E3s binds to F-box proteins. There are a gadzillion-squared F-box proteins in the genome. These addapters then recruit proteins targetted for destruction to the E2-E3(Cullen)-F box protein complex. Are you still conscious? Then as part of their function, Cullins get nedylated. What? Yes I neddilate, you neddilate ... you know the verb to neddilate. Anway this complex (or glop) of E2-neddilated-E3-F-box-soon-to-be-destrayed-proteins may even directly bind to the proteosome (i.e. the supper huge trash bin of the cell).

Then there are Dufs, or de-ubiquitin factors. How many Dufs in your genome? He showed some phylogenitic tree of the Duf family and it looked like a willowtree (or a medusa).

OK now what the hell are Uba, Uim, Ubx, Ubl? ... you can see why my mind is in a million pieces. (Ok I'm exagerating, but at least I didn't claim to be an ex-con.)

Anyways ... these are domains found in various proteins.

Uba: ubiquitin associating domains
Uim: ubiquitin interacting motifs
Ubx: a domain that shares the same structure as ubiquitin
Ubl: ubiquitin like domain that not only shares the same fold as ubiquitin butr also has sequence similarity.

So it would seem that about one third* of the genome is there to destroy the products of the other 2/3. Ubiquitin's second function is to blowup your brain.

Arrggghhhh! Cannn't ... thinnnnnk ... muuusssst ... shhuuuttt ... doooowwwwwnnnnnn ...

*slight exageration.