What is Ubiquitylation

Ubiquitylation, also known as ubiquitination, is a post-translational modification process in which a small protein called ubiquitin is covalently attached to target proteins. This process plays a crucial role in various cellular functions, including protein degradation, signal transduction, DNA repair, and protein trafficking.

The attachment of ubiquitin to target proteins involves a series of enzymatic reactions mediated by three main classes of enzymes:

1. **Ubiquitin-Activating Enzymes (E1)**: These enzymes activate ubiquitin by forming a high-energy thioester bond between the C-terminal glycine of ubiquitin and a cysteine residue in the E1 enzyme. This step requires ATP hydrolysis.

2. **Ubiquitin-Conjugating Enzymes (E2)**: Activated ubiquitin is then transferred from the E1 enzyme to a cysteine residue in the E2 enzyme via a trans-thiolation reaction.

3. **Ubiquitin Ligases (E3)**: Ubiquitin ligases facilitate the transfer of ubiquitin from the E2 enzyme to the target protein, leading to the formation of an isopeptide bond between the C-terminal glycine of ubiquitin and a lysine residue on the target protein. Ubiquitin ligases confer specificity to the ubiquitylation process by recognizing and binding specific target proteins.

The attachment of a single ubiquitin molecule to a target protein is known as monoubiquitylation. However, ubiquitin itself contains seven lysine residues (K6, K11, K27, K29, K33, K48, and K63), as well as its N-terminal methionine residue, which can serve as acceptor sites for additional ubiquitin molecules. This results in the formation of polyubiquitin chains, which can adopt different linkage types depending on which lysine residue is used for chain elongation. For example, polyubiquitin chains linked through K48 are often associated with targeting proteins for proteasomal degradation, whereas K63-linked chains are involved in non-proteolytic processes such as DNA repair and endocytosis.

Once ubiquitin is attached to the target protein, the modified protein can be recognized by ubiquitin-binding proteins that mediate various cellular processes. For example, proteins tagged with K48-linked polyubiquitin chains are targeted to the proteasome for degradation, while proteins modified with K63-linked chains are involved in signaling pathways, protein trafficking, and DNA repair.

Overall, ubiquitylation is a highly regulated process that controls the fate and function of proteins within the cell, playing critical roles in cellular homeostasis, signaling, and responses to cellular stress and environmental cues.