Within the bustling metropolis of your cells, amidst the teeming throngs of proteins, reside the E3 ligases – the silent guardians of cellular order. These are not your average bouncers. Understanding the interaction between E3 ligases and their target proteins holds immense potential for unlocking new solutions in medicine and beyond.
What are E3 Ligases?
Imagine E3 ligases as molecular matchmakers, pairing unwanted proteins with a tiny protein tag called ubiquitin. This tag acts as a “demolition order,” marking the protein for targeted removal.
What is the function of the E3 ligases?
E3 ligases play a crucial role in maintaining cellular homeostasis by:
- Cleaning up misfolded or damaged proteins: These rogue citizens can disrupt cellular functions and contribute to diseases like neurodegenerative disorders. E3 ligases ensure their timely removal, keeping the cellular machinery running smoothly.
- Regulating protein levels: Just like controlling traffic flow in a city, E3 ligases fine-tune cellular activities by removing proteins that regulate specific processes, like cell division or gene expression. This ensures a delicate balance within the cellular ecosystem.
- Defending against invaders: This defense mechanism serves as a crucial line of defense against microbial threats.
How many E3 ligases have been discovered?
With over 600 identified in humans alone! Each E3 ligase has its own set of preferences, recognizing specific target proteins through unique interactions. This diverse cast of E3 ligases ensures precise and selective removal of unwanted residents from the cellular cityscape.
What are the diseases associated with E3 ligases?
The E3 ligase system malfunctions, the consequences can be dire. Mutations in E3 ligase genes can lead to:
- Cancer: Dysfunctional E3 ligases can allow harmful proteins to accumulate, promoting uncontrolled cell growth and tumor formation.
- Neurodegenerative diseases: Impaired protein degradation by E3 ligases can lead to the buildup of misfolded proteins. A hallmark of conditions like Alzheimer’s and Parkinson’s disease.
- Autoimmune diseases: E3 ligases play a role in immune regulation. Malfunction can lead to the accumulation of self-reactive immune cells, contributing to autoimmune conditions like rheumatoid arthritis.
What E3 Ligases are used in PROTACs?
PROTACs (Proteolysis-Targeting Chimeras) are emerging therapeutic molecules that hijack the E3 ligase system. They act like molecular bridges, linking a disease-causing protein to an E3 ligase. Ultimately leading to the targeted degradation of the unwanted protein. Several E3 ligases, including VHL and CRBN, are being actively explored for the development of PROTACs for various diseases.
The intricate world of E3 ligases and their target proteins offers a fascinating glimpse into how cells maintain order and fight off threats. Understanding this complex dance holds immense promise for developing new therapeutic approaches for a wide range of diseases. As research delves deeper into this cellular machinery. In medicine and biotechnology and paving the way for a healthier future, we can expect groundbreaking advancements.
Ubiquitin modification plays an important role in the post-translational modification of proteins. In cells, various E3 ubiquitin ligases catalyze the polyubiquitination of specific proteins, resulting in their degradation in the proteasome, which is the main way proteins are degraded in cells. Proteolysis targeting chimeras is a chemical molecule that contains two different ligands at each end: a ligand that binds the E3 ligase (pink triangle below) and a ligand that binds intracellular proteins (TP: target protein below) (yellow circle below). The two ligands link by a linker. PROTAC can be recycl and is not degrad by proteasomes.
E3 ligase and Purification Services
The E3 ubiquitin ligases are classified into three major types: the really interesting new gene (RING), the homologous to the E6-AP carboxyl terminus (HECT) and the RING-between-RING (RBR) types of E3 ligases.
RING E3s are characteriz by the presence of a zinc-binding domain call RING or by a U-box domain.
The conserved HECT domain is characterized by a bi-lobar architecture: the N-terminal lobe and the C-terminal lobe. The two lobes are tether by a flexible hinge region. Based on the N-terminal extensions, human HECTs can be classified into three subfamilies: (1) Nedd4 family, which contains tryptophan-tryptophan (WW) motifs, (2) HERC (HECT and RCC1-like domain) family, which possesses one or more regulators of chromosome condensation 1 (RCC1)-like domains (RLDs), and (3) “other” HECTs that contain various domains. The RBR name derives from the presence of two predicted RING domains (RING1 and RING2), which separates by an in-between-RING domain (IBR).
Source from Profacgen
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