What does an E3 ligase do?
Ubiquitin E3 ligases control every aspect of eukaryotic biology by promoting protein ubiquitination and degradation. At the end of a three-enzyme cascade, ubiquitin ligases mediate the transfer of ubiquitin from an E2 ubiquitin-conjugating enzyme to specific substrate proteins.
What is Cereblon E3 ligase?
The E3 ubiquitin ligase component, Cereblon, is an evolutionarily conserved regulator of Wnt signaling | Nature Communications.
What is an E3 ligand?
Related Products. PDF 1.28 MB. A PROTAC (Proteolysis Targeting Chimeric Molecule) is a protein degrader comprised of a ligand for E3 ligase (E3 ligase binder), a linker and a ligand for target protein (target binder).
How does cereblon work?
Cereblon forms part of an E3 ubiquitin ligase complex, which is involved in regulating protein degradation. Thalidomide is proposed to bind to cereblon inhibiting its function, which ultimately may lead to abnormal signaling events in the embryo (Ito et al., 2010).
What do PROTACs do?
PROTACs are designed to take advantage of the cell’s waste disposal system that removes unneeded proteins. This system, known as the proteasome, is important for the cell to remove unneeded or damaged proteins and recycle their building blocks to make new proteins.
Is VHL an E3 ligase?
VHL and CRBN are also the two most popular E3 ligases being recruited by bifunctional Proteolysis-targeting chimeras (PROTACs) to induce ubiquitination and subsequent proteasomal degradation of a target protein.
Which family of E3 ligases transfers ubiquitin directly from E2 to the substrate?
RING-type E3s
HECT-type E3s function as covalent intermediates in the ubiquitination pathway as ubiquitin is first transferred to the active site Cys of E3 via a transthiolation before conjugation to substrate. RING-type E3s instead mediate the transfer of ubiquitin directly from E2~Ub to substrate.
What type of E3 ligase is MDM2?
E3 ubiquitin ligase
Mouse double minute 2 (MDM2) is an E3 ubiquitin ligase that is over-expressed in many cancers and regulates target proteins through ubiquitination.
Does thalidomide bind Cereblon?
Thalidomide binds to the cereblon (CRBN) protein within the CRL4 E3 ubiquitin ligase complex. CRBN is a key molecule for thalidomide-induced teratogenesis (Ito et al, 2010).
Are there any FDA approved PROTACs?
Although there is no drug approved by the FDA so far, PROTAC will eventually usher in its era after more than 20 years of technical accumulation.
Is VHL a ubiquitin ligase?
Von Hippel-Lindau (VHL) is an E3 ubiquitin ligase that targets proteins, including HIF-1α, for proteasomal degradation. VHL and HIF regulate the balance between glycolysis and oxidative phosphorylation, which is critical in highly dynamic T cells.
What is RING E3 ligase?
The RING-domain E3 ligases (RING E3s), a group of E3 ligases containing one or two RING finger domains, are involved in various cellular processes such as cell proliferation, immune regulation, apoptosis, among others.
How does Cereblon work?
Why are PROTACs better than inhibitors?
The PROTAC advantage Unlike conventional inhibitor drugs, PROTACs do not require a deep hydrophobic binding pocket or active site. This permits development of novel ligands that can bind to other areas of the target protein.
How many E3 ligases are in the human body?
Although there are only 2 E1 and 30-50 E2 genes, there are over 600 human E3 ligase genes whose diversity is accounted for by three different types of catalytic domains: Really Interesting New Gene (RING), Homologous to E6-AP Carboxyl Terminus (HECT), or Ring-Between-Ring (RBR) (Zheng and Shabek, 2017).
What is the role of E3 ligase SMURF1 in Wolfram syndrome?
The E3 ligase Smurf1 regulates Wolfram syndrome protein stability at the endoplasmic reticulum. J Biol Chem. 2011;286:18037–47. 65. Fei C, He X, Xie S, Miao H, Zhou Z, Li L. Smurf1-mediated axin ubiquitination requires Smurf1 C2 domain and is cell cycle-dependent.
What is the target protein for ubiquitin ligase SMURF1?
Li S, Lu K, Wang J, An L, Yang G, Chen H. et al. Ubiquitin ligase Smurf1 targets TRAF family proteins for ubiquitination and degradation. Mol Cell Biochem. 2010;338:11–7.
Where is SMURF1 found in the human body?
Human SMURF1 ( SMAD-specific E3 ubiquitin protein ligase 1) is located on chromosome 7q22.1. SMURF1, as one of Nedd4 family, expresses in many tissues, including the nervous system, bone, lung, and reproductive organs [ 7, 8, 9, 10 ].
What is the role of SMURF1 in breast cancer?
Nie J, Liu L, Wu M, Xing G, He S, Yin Y, et al. HECT ubiquitin ligase Smurf1 targets the tumor suppressor ING2 for ubiquitination and degradation. FEBS Lett. 2010;584:3005–12. Yang H, Yu N, Xu J, Ding X, Deng W, Wu G, et al. SMURF1 facilitates estrogen receptor a signaling in breast cancer cells. J Exp Clin Cancer Res. 2018;37:24.