Post-Translational Modifications (PTMs): PTMs refer to the chemical modifications that occur on protein side chains or termini after protein synthesis. These modifications significantly expand the genetic coding capacity, endowing proteins with diverse functionalities. PTMs not only enhance protein diversity but also play crucial roles in processes such as cell signaling, protein folding, stability, degradation, cell cycle regulation, and gene expression.
Ubiquitination
Ubiquitination is a common PTM that involves attaching a small protein, ubiquitin, to target proteins, thereby regulating their fate and function. Ubiquitination encompasses both single ubiquitin attachment and the formation of polyubiquitin chains, which enable a wide range of biological functions within the cell.
Types of Ubiquitination
- Monoubiquitination: A single ubiquitin molecule attaches to a lysine residue on the target protein, often associated with endocytosis, DNA repair, signal transduction, and gene expression regulation.
- Polyubiquitination: Multiple ubiquitin molecules form a chain via lysine residues (e.g., Lys48 or Lys63). Lys48-linked chains usually tag proteins for proteasomal degradation, while Lys63-linked chains are involved in signaling, protein complex assembly, and endocytosis.
- Mixed Ubiquitination: Chains with varying types of ubiquitin linkages, adding complexity to ubiquitin signaling pathways.
Biological Roles of Ubiquitination
- Protein Degradation: Ubiquitination tags damaged or unnecessary proteins for proteasomal degradation, maintaining cellular protein homeostasis.
- Signal Transduction: Acts as a molecular switch, regulating pathways such as NF-κB and Wnt/β-catenin by modulating protein stability and activity.
- Gene Expression: Ubiquitination of nuclear proteins, such as histones H2A and H2BK, impacts chromatin structure and transcriptional activity.
- Cell Cycle and DNA Repair: Regulates key proteins during the cell cycle and marks damaged DNA for repair initiation.
- Autophagy: Selectively degrades damaged proteins and organelles through ubiquitin-mediated autophagy pathways.
Key Examples of Ubiquitination
- Mdm2 and p53: The E3 ligase Mdm2 ubiquitinates p53, targeting it for proteasomal degradation, thereby regulating cell cycle checkpoints.
- Notch Receptor: Ubiquitination activates Notch by releasing its intracellular domain, which translocates to the nucleus to control gene expression.
- HIV-1 Nef Protein: The Nef protein exploits the host ubiquitin system to downregulate MHC I molecules, helping the virus evade immune surveillance.
Deubiquitination
Deubiquitination is the reverse process of ubiquitination, catalyzed by a family of enzymes called Deubiquitinating Enzymes (DUBs). These enzymes remove ubiquitin molecules from proteins, restoring their original state or modifying ubiquitin chains. DUBs are categorized into several families based on structure and catalytic mechanisms.
Roles of Deubiquitination in Cellular Processes
- Cell Cycle Regulation: DUBs such as USP7 prevent premature degradation of cyclin-dependent kinase inhibitors, ensuring proper cell cycle progression.
- Signal Transduction: A20 deubiquitinates key molecules in the NF-κB pathway, terminating excessive signaling to prevent chronic inflammation.
- DNA Repair: DUBs enhance the recruitment of repair proteins like BRCA1 to damaged sites, facilitating genome stability.
- Immune Response: USP25 stabilizes critical factors for Th17 cell differentiation, aiding adaptive immunity.
- Protein Homeostasis: DUBs like USP14 optimize protein turnover, balancing synthesis and degradation for cellular health.
With ubiquitination and deubiquitination intertwined across key biological processes, these mechanisms are central to protein regulation, signaling, and disease understanding.
