Question

Explain the role of ubiquitination in the regulation of cellular protein levels.

Answer 1

Ubiquitination is a 76-amino acid protein that can be ubiquitously expressed in all tissues. It's function is ligating Ub molecule(s) to a substrate protein, thereby regulating protein stability and translocation. It can be considered as one of the most common forms of post translational protein modification.

Ubiquitination requires ATP and involves three enzymatic reactions requiring E1, E2, and E3 ligases. In this process E3 ligase conjugates Ub to lysine (K) residues of the substrate, forming a Ub chain by linking Ub molecules through one of the lysine residues or the N-terminal methionine residue (M1). These lysine residues are K6, K11, K27, K29, K33, K48, and K63, among these K48 linkage is the most commonly found Ub chain and help protein degradation in proteasom. Transcriptional regulation, DNA damage repair, and membrane-associated endocytosis are done by Monoubiquitination.

A large set of proteases which can remove Ub molecules from target substrates to reverse ubiquitination are called as Deubiquitinating enzymes, and it has two groups---cysteine proteases and metalloproteases. The Ub E3 ligases and DUBs are important for regulating protein and for maintaining the free Ub pool. Hakai ( Ub E3 ligase) targets tyrosine phosphorylated E-cadherin, thus regulating its endocytosis and stability. Then phosphorylation enhances the E-cadherin binding with Hakai. However, hakai is not the only Ub E3 ligase that has been connected to AJs protein degradation. One substrate can be modulated by multiple Ub E3 ligases. Ubiquilin 1 has two terminals-- N-terminal (UBL) and C-terminal (UBA) which will help the ubiquitinated proteins for degradation by the proteasome. The effects of these Ub E3 ligases on E-cadherin protein levels may influence other genes related to the targeted transcriptional factors. MDM2 interacts with E-cadherin and regulates its ubiquitination, and it plays a major role in the regulation of E-cadherin transcriptional repressors eg. Slug and Snail. MDM2 can also controls the tumor suppressor p53 as well as p53-dependent Slug and Snail ubiquitination and degradation by the proteasome system.

Ubiquitin acts as a tag that signals the protein-transport machinery to ferry the protein to the proteasome for degradation. SCF complexes are known to ubiquitinate a wide variety of membrane proteins to regulate processes, such as cell cycle, signal transduction, and protein quality control