What Protein Structures Can Be Ubiquitinated?

Ubiquitination is a post-translational modification (PTM) that involves the addition of one or more ubiquitin proteins to a substrate protein. Ubiquitin is a small regulatory protein that can covalently bind with other proteins. Ubiquitination can impact the degradation, localization, activity, and interactions of proteins. Understanding which protein structures can be ubiquitinated requires an understanding of the mechanism and target characteristics of ubiquitination.

 

Mechanism of Ubiquitination

1. Ubiquitin Activation

Ubiquitin is first activated by the ubiquitin-activating enzyme (E1) and forms a high-energy thioester bond with it.

 

2. Ubiquitin Conjugation

The activated ubiquitin is then transferred to the ubiquitin-conjugating enzyme (E2).

 

3. Ubiquitin Ligation

The ubiquitin ligase (E3) identifies specific substrate proteins and assists in transferring ubiquitin from E2 to the substrate protein.

 

Ubiquitinatable Protein Structures

1. Target Site Specificity

(1) Lysine Residues

The most common targets for ubiquitination are lysine (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 cysteine.

 

2. Ubiquitination Site Sequence

Certain protein sequences are more susceptible to ubiquitination than others. Although there is no absolute sequence specificity, research shows that peptide segments with specific sequences (such as PXXLXQ) easily bind with E3 ubiquitin ligase, promoting ubiquitination.

 

3. Accessibility of Structure

The tertiary structure of a protein can affect the accessibility of specific lysine residues. Ubiquitination can only occur when E2 ubiquitin-conjugating enzyme and E3 ubiquitin ligase can access these residues.

 

4. Protein Flexibility and Dynamics

Regions with greater flexibility or parts of the protein with some structural dynamics are more likely to be ubiquitinated, as they can more easily accommodate the active sites of E2 and E3 enzymes.

 

5. Precursor State of Modification

The other post-translational modification states of a protein, such as phosphorylation, acetylation, etc., can sometimes increase the chance of a protein being ubiquitinated, as they can change the charge, conformation, or affinity of the protein for the E3 ubiquitin ligase.

 

Ubiquitination can occur on various types of protein structures, but it often prefers lysine residues that can interact with E2 and E3 enzymes in terms of spatial structure. The ubiquitination status and function of a protein are influenced by its own structural characteristics as well as various factors in the cellular environment.