I’ve just learned about ubiquitin, proteasome and their functions. As usual, wikipedia is useless with its hard words, so I resort to asking here.
Can ubiquitin detect its own malfunction, or another ubi’s fault?
There are thousands of proteins around. Each one can malfunction is numerous ways. How can ubi know all the cases?
Given its (& proteasome’s) importance, what’s the worst bio-weapon mechanism you can think of?
Cheers!
Ubiquitin and related molecules are just the “tags” that get attached to proteins to mark them for degradation by the proteasome. The important players that decide which proteins get ubiquitinated are enzymes called E3 ligases that recognise the target molecules and transfer the ubiquitin moiety from the E2 enzyme to the target molecule. The human genome encodes 600 or more different E3 ligases, and many of these are complicated multiprotein complexes. They do much more than just remove misfolded proteins. For example, they play also an important role in the regulation of the cell cycle and in many signalling systems.
Misfolded proteins may be recognised by “floppy” unfolded termini. The ubiqitination of other proteins is regulated by specific serine and threonine phosphorylations. It is really a very complex story, and overmuch a topic of ongoing research.
Ah, thank you. So this mechanism can only deal with misfolded proteins, and among them the type that have weird ends. If a protein has very wrong middle sites but not-floppy termini then it’ll escape fate. Maybe that’s why we still suffer from so many diseases?
Since enzymes are also proteins, I guess proteasome has this mechanism that whenever it detects any wandering ubiquitin, it checks whether that ubi is attached to E2 or any other proteins. If the latter case is true, destruction awaits. But if it’s E2 then protea will release the grip? Then… if a bio-agent disguises its terminus with surface just like E2, then even in the case it’s tagged with ubi, it’ll survive nonetheless?
It’s more complicated - since ubiquitin also contains lysine residues, although in each step only one ubiquitin unit is added, eventually whole chains of ubiquitins are attached, and these can even be branched. A single ubiquitin unit is usually not sufficient to target a protein to the proteasome, and only certain polyubiquitin chain geometries do so, while other geometries have different functions ( see Polyubiquitin chains: functions, structures, and mechanisms - PMC and related articles)