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.
Is VHL a ligase?
The main action of the VHL protein is thought to be its E3 ubiquitin ligase activity that results in specific target proteins being ‘marked’ for degradation. While HIFs are mostly active in hypoxic conditions, VHL-defective renal carcinoma cells show constitutive activation of HIF even in oxygenated environments.
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.
Is Cereblon an E3 ligase?
Cereblon forms an E3 ubiquitin ligase complex with damaged DNA binding protein 1 (DDB1), Cullin-4A (CUL4A), and regulator of cullins 1 (ROC1). This complex ubiquitinates a number of other proteins. The net result is that this ubiquitin ligase complex is important for limb outgrowth in embryos.
What is Von Hippel-Lindau disease?
Von Hippel-Lindau syndrome (VHL) is a hereditary condition associated with tumors arising in multiple organs. VHL-related tumors include hemangioblastomas, which are blood vessel tumors of the brain, spinal cord, and retina.
Why is VHL a tumor suppressor?
The VHL protein likely plays a role in other cellular functions, including the regulation of other genes and control of cell division. Based on this function, the VHL protein is classified as a tumor suppressor, which means it prevents cells from growing and dividing too rapidly or in an uncontrolled way.
What is the function of VHL?
What does E3 do in ubiquitination?
A ubiquitin ligase (also called an E3 ubiquitin ligase) is a protein that recruits an E2 ubiquitin-conjugating enzyme that has been loaded with ubiquitin, recognizes a protein substrate, and assists or directly catalyzes the transfer of ubiquitin from the E2 to the protein substrate.
How does Thalidomide bind with Cereblon?
Thalidomide directly binds cereblon (CRBN), which was originally reported as a cerebral protein associated with mild mental retardation25,26. Thalidomide is suggested to initiate its teratogenic effects by binding to CRBN and modulating the associated ubiquitin ligase activity25.
What is the function of Cereblon?
Cereblon (CRBN) is the substrate receptor of the cullin 4-RING E3 ligase complex and has been employed for targeted protein degradation in the treatment of cancers. However, its normal physiological functions and molecular mechanism in the regulation of DNA damage response are largely unknown.
Is VHL fatal?
Although they are typically noncancerous, they can cause serious or life-threatening complications. Hemangioblastomas that develop in the brain and spinal cord can cause headaches, vomiting, weakness, and a loss of muscle coordination (ataxia).