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Ubiquitination

Ubiquitin is a small protein found in most eukaryotic cells. Its main function is to mark proteins that need to be broken down for hydrolysis. When a protein with ubiquitin is moved to a protease barrel, the protease hydrolyzes the protein. Ubiquitin can also label transmembrane proteins, such as receptors, to remove them from the cell membrane.

Ubiquitin model

Ubiquitination

Ubiquitination is an enzymatic, post-translational protein modification (PTM) process in which the carboxyl group of the terminal glycine from the diglycine phantom of the activated ubiquitin is linked to the lysine ε amino group of the modified protein to form an amide bond.

The process of labeling proteins with ubiquitin (ubiquitination) involves a series of steps:

1. Activation: Ubiquitin is activated by a two-step reaction involving ubiquitin activase E1 and requires ATP for energy. In the first step, ubiquitin reacts with ATP to form the ubiquitin-adenylate complex. The second step is the transfer of ubiquitin, that is, ubiquitin is separated from AMP and transferred to the cysteine residue of E1, and the carboxyl terminus of ubiquitin is linked to the sulfhydryl group of cysteine in E1 enzyme by a thioester bond.

2. Binding: E1 transfers the activated ubiquitin to ubiquitin-binding enzyme E2 via a thioesterification reaction.

3. Connection: Ubiquitin ligase E3 ubiquitin cascade catalyzed the final step, will combine to E2 protein ubiquitin transferred to the target, the target protein of a lysine and ubiquitin carboxyl end a glycine by heterogeneous peptide bond connection, this step usually needs more than 100 E3 ligase catalytic, E3 ligase has substrate recognition effect And can interact with E2 and substrate, some E3 can also activate E2 activity.

In the ubiquitination cascade, each step is divided into different levels. E1 can bind multiple E2, and E2 can bind multiple E3. This strict stratification phenomenon enables cells to conduct more delicate regulation of ubiquitination.

Ubiquitin-like proteins (ULPs) also modify proteins through the E1-E2-E3 cascade system, but there are some differences with ubiquitin-like proteins.

E4 ubiquitin chain extender, which extends ubiquitin on a monoubiquitinated protein produced by E3 ubiquitin ligase.

Ubiquitination system

E3 ubiquitin ligases have one of two domains:

1. HECT (Homologous to the E6-AP Carboxyl Terminus) domain

2. RING (Really Interesting New Gene) domain (or the closely related U-box domain)

Ubiquitin is eventually transferred to protein substrates in two ways:

1. Direct transfer from E2-binding enzyme to protein substrate (catalyzed by the RING domain of E3 enzyme)

2. It is then transferred to the protein substrate by E3 ligase (catalyzed by the HECT domain of E3 enzyme). Prior to transferring to the protein substrate, ubiquitin forms an E3-ubiquitin complex by a thioester bond with a conserved cysteine residue in the HECT domain of E3 enzyme.

Deubiquitination

Protein ubiquitination is a reversible process, which is called Deubiquitination, mediated by a class of proteolytic enzymes, Deubiquitinating enzymes (DUBs).

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