How does ubiquitin recognize misfolded proteins?

Question

Misfolded proteins are tagged by ubiquitin and then are destroyed by proteasomes. How does ubiquitin know which protein to tag?

Answer 1

Great question! I remember being curious about this when I learned about ubiquitin dependent proteolysis. As you may have guessed, the actual pathway is a bit more complex than just ubiquitin attaching itself to a protein. In order to latch on to a target protein, ubiquitin needs help from an elite team of enzymes (OK, I made up the elite part) called E1, E2 and E3. Each of these enzymes plays a different role:

E3 (also called ubiquitin ligase): This enzyme is the one which recognizes the proteins to be marked for death by ubiquitin. Most cells contain a large number of E3 enzymes which are capable of recognizing specific proteins. E3 ligases mostly recognize target proteins by amino acid sequence, but I believe some can actually recognize particular 3D structures on their target protein as well, which is pretty cool.

E2 (AKA ubiquitin conjugating enzyme): These act as a sort of middle man between E3, the substrate, and E1. Ubiquitin ligase (E3) recognizes a target protein and locks on to it. Then, E3 recruits an E2 enzyme by binding to it. E2 accepts a "primed" ubiquitin from an E1 protein, then transfers it to the target protein. This occurs repeatedly, creating the ubiquitin chain which marks the target protein for death.

E1 (Ubiquitin-activating enzyme): This enzyme does exactly what its name says, binding to an ubiquitin and "priming" or activating it (using ATP) so that it's ready to do its thing.

I hope this answer was helpful!

-Bryce

Answer 2

There are termination signals that tell the cell when to tag a molecule with ubiquitin and target it for degradation. You mentioned misfolded proteins, which is indeed a signal for degradation. This may be due to the fact that the hydrophobic core is now being exposed rather than being tucked away the inside of the protein.

Two other signals for degradation are the N-end rule and PEST sequences. The N-end rule is when there are specific amino acids located on the N terminal of a protein it will have a shorter half life than say other amino acids. The shorter the half life means that the protein will be degraded much quicker than a protein with a long half life. PEST sequences are when proteins are enriched in Proline (P), Glutamate (E), Serine (S), and Threonine (T) , that they will have shorter half lives. These letters are the one letter abbreviation of the amino acids.