Target type: molecularfunction
Catalysis of the transfer of NEDD8 from one protein to another via the reaction X-NEDD8 + Y = Y-NEDD8 + X, where both X-NEDD8 and Y-NEDD8 are covalent linkages. [GOC:mah]
NEDD8 transferase activity is a crucial molecular process involved in the post-translational modification of target proteins with the ubiquitin-like protein NEDD8. This conjugation, known as NEDDylation, is a dynamic and reversible process with significant regulatory roles in diverse cellular functions.
NEDD8 transferase enzymes, also called E3 ligases, are responsible for mediating the final step of NEDDylation. They bring together the NEDD8 protein and a target protein, facilitating the formation of an isopeptide bond between the two. This conjugation event requires the coordinated action of three enzyme families: E1 (NEDD8 activating enzyme), E2 (NEDD8 conjugating enzyme), and E3 (NEDD8 ligase).
The E1 enzyme activates NEDD8 by adenylating it and then transferring it to the E2 enzyme. The E2 enzyme, in turn, carries the activated NEDD8 and interacts with the E3 ligase. The E3 ligase recognizes and binds to specific target proteins, bringing them into close proximity with the E2-NEDD8 complex. This interaction enables the transfer of NEDD8 from the E2 enzyme to the target protein, forming the NEDDylated protein.
The molecular function of NEDD8 transferase activity encompasses several key aspects:
* **Substrate Specificity:** E3 ligases exhibit high specificity for their target proteins, ensuring that only specific proteins are NEDDylated. This specificity arises from the unique interaction domains present on both the E3 ligase and its target protein.
* **Ubiquitin-like Conjugation:** NEDD8 transferase activity involves the covalent attachment of NEDD8 to a target protein, similar to the conjugation of ubiquitin to proteins. However, NEDD8 differs from ubiquitin in its structural and functional properties.
* **Regulation of Protein Activity:** NEDDylation can modify the activity of target proteins by various mechanisms, including:
* **Altering protein conformation:** NEDDylation can change the three-dimensional structure of a protein, affecting its ability to interact with other molecules.
* **Modulating protein stability:** NEDDylation can influence the stability of a protein by affecting its degradation rate.
* **Regulating protein localization:** NEDDylation can influence the cellular compartment where a protein resides.
* **Cellular Signaling:** NEDDylation plays a vital role in regulating various cellular signaling pathways, including the cell cycle, DNA damage response, and immune signaling.
Overall, the molecular function of NEDD8 transferase activity is to catalyze the conjugation of NEDD8 to specific target proteins, thereby regulating their activity, stability, and localization. This process is essential for maintaining proper cellular function and homeostasis.'
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Protein | Definition | Taxonomy |
---|---|---|
NEDD8-activating enzyme E1 catalytic subunit | A NEDD8-activating enzyme E1 catalytic subunit that is encoded in the genome of human. [PRO:DNx, UniProtKB:Q8TBC4] | Homo sapiens (human) |
NEDD8-conjugating enzyme Ubc12 | A NEDD8-conjugating enzyme Ubc12 that is encoded in the genome of human. [PRO:DNx, UniProtKB:P61081] | Homo sapiens (human) |
NEDD8-activating enzyme E1 catalytic subunit | A NEDD8-activating enzyme E1 catalytic subunit that is encoded in the genome of human. [PRO:DNx, UniProtKB:Q8TBC4] | Homo sapiens (human) |
NEDD8-conjugating enzyme Ubc12 | A NEDD8-conjugating enzyme Ubc12 that is encoded in the genome of human. [PRO:DNx, UniProtKB:P61081] | Homo sapiens (human) |
Compound | Definition | Classes | Roles |
---|---|---|---|
candesartan cilexetil | candesartan cilexetil: a prodrug which is metabolized to an active form candesartan to exert its biological effects | biphenyls | |
mitoxantrone | mitoxantrone : A dihydroxyanthraquinone that is 1,4-dihydroxy-9,10-anthraquinone which is substituted by 6-hydroxy-1,4-diazahexyl groups at positions 5 and 8. Mitoxantrone: An anthracenedione-derived antineoplastic agent. | dihydroxyanthraquinone | analgesic; antineoplastic agent |
gartanin | gartanin : A member of the class of xanthones that is 9H-xanthen-9-one substituted by hydroxy groups at positions 1, 3, 5 and 8 and prenyl groups at positions 2 and 4. | polyphenol; xanthones | antineoplastic agent; plant metabolite |
pevonedistat | pevonedistat : A pyrrolopyrimidine that is 7H-pyrrolo[2,3-d]pyrimidine which is substituted by a (1S)-2,3-dihydro-1H-inden-1-ylnitrilo group at position 4 and by a (1S,3S,4S)-3-hydroxy-4-[(sulfamoyloxy)methyl]cyclopentyl group at position 7. It is a potent and selective NEDD8-activating enzyme inhibitor with an IC50 of 4.7 nM, and currently under clinical investigation for the treatment of acute myeloid leukemia (AML) and myelodysplastic syndromes. pevonedistat: a potent and selective inhibitor of NAE (NEDD8-activating enzyme) | cyclopentanols; indanes; pyrrolopyrimidine; secondary amino compound; sulfamidate | antineoplastic agent; apoptosis inducer |