Ubiquitination is a protein post-translational modification (PTM) that involves adding one or more ubiquitin proteins to a substrate protein. Ubiquitin is a small regulatory protein that can be covalently bound to other proteins. Ubiquitination can affect protein degradation, location, activity, and protein-protein interactions. Understanding which protein structures can be ubiquitinated requires a starting point with the mechanisms and target properties of ubiquitination.
Mechanisms of ubiquitination
1.Ubiquitin activation: Ubiquitin is first activated by the ubiquitin-activating enzyme (E1), with which it forms a high-energy thioester bond. 2.Ubiquitin binding: Activated ubiquitin is then transferred to the ubiquitin-binding enzyme (E2). 3.Ubiquitin ligation: Ubiquitin ligase (E3) recognizes specific substrate proteins and assists in the transfer of ubiquitin from E2 to substrate proteins. Protein structures that can be ubiquitinated:
1.Target site specificity
1.Lysine residues: The most common target sites for ubiquitination are lysine (K) residues. The C-terminal glycine of ubiquitin forms a covalent bond with the side-chain amino group of lysine. 2.Other residues: While lysine is the most common target, ubiquitin can also be attached to other amino acid residues such as serine, threonine, and cysteine2.Ubiquitination site sequence:
Certain protein sequences are more susceptible to ubiquitination than others. Although there is no absolute sequence specificity, peptides containing specific sequences (e.g., pxxLXQ) have been shown to easily bind to E3 ubiquitin ligases and promote ubiquitination.
3.Accessibility of the structure:
The structure of a protein affects the accessibility of specific lysine residues. Ubiquitination can only occur if these residues are accessible to E2 ubiquitin-conjugating enzyme and E3 ubiquitin ligase.
4.Flexibility and dynamics of proteins:
Regions with high flexibility or some structural dynamics of proteins are more susceptible to ubiquitination because they are more easily adapted to the active sites of E2 and E3 enzymes.
5.Modified precursor state:
Other post-translational modification states of proteins, such as phosphorylation, acetylation, etc., can sometimes increase the chance of a protein being ubiquitinated because they can alter the protein's charge, conformation, or affinity with E3 ubiquitin ligase.
Ubiquitination can occur on many different types of protein structures, but this process tends to favor lysine residues that can interact with E2 and E3 enzymes in a spatial structure. The ubiquitination state and function of proteins are influenced by their own structural characteristics as well as by a variety of factors in the cellular environment.