positive regulation of protein neddylation

Definition

Target type: biologicalprocess

Any process that activates or increases the frequency, rate or extent of protein neddylation. [GOC:obol]

Positive regulation of protein neddylation is a crucial biological process involving the attachment of NEDD8 (Neural precursor cell expressed, developmentally downregulated 8), a ubiquitin-like protein, to target proteins. This process, known as neddylation, is essential for the regulation of diverse cellular functions, including cell cycle progression, DNA replication, and protein degradation.

The neddylation pathway is initiated by the activation of NEDD8, which involves the formation of a thioester bond between NEDD8 and the E1 enzyme, NEDD8 activating enzyme (NAE). This activated NEDD8 is then transferred to the E2 enzyme, NEDD8 conjugating enzyme (UBE2F), also known as UBC12. Finally, the E3 ligase, a protein complex containing Cullin and RING-box protein 1 (RBX1), facilitates the transfer of NEDD8 from the E2 enzyme to a lysine residue on the target protein.

Neddylation positively regulates the activity of Cullin-RING ligases (CRLs), a family of E3 ubiquitin ligases that play a central role in protein degradation. CRLs are responsible for recognizing and targeting proteins for ubiquitination, a process that marks them for degradation by the proteasome. The neddylation of Cullins enhances the activity of CRLs by promoting their assembly and stabilizing their interaction with the substrate receptor proteins.

Positive regulation of protein neddylation can occur through various mechanisms, including:

1. Increased expression or activity of NAE, the E1 enzyme responsible for activating NEDD8.
2. Increased expression or activity of UBE2F, the E2 enzyme responsible for transferring activated NEDD8 to target proteins.
3. Increased expression or activity of CRLs, the E3 ligases responsible for catalyzing the neddylation reaction.
4. Increased expression or activity of specific substrate receptor proteins that recruit target proteins to CRLs.

Conversely, negative regulation of protein neddylation can occur through mechanisms such as:

1. Inhibition of NAE activity by NEDD8 deconjugating enzymes (DENs), which remove NEDD8 from target proteins.
2. Inhibition of CRL assembly or activity by specific inhibitors or mutations.

The dysregulation of protein neddylation has been implicated in various diseases, including cancer, neurodegenerative diseases, and inflammatory disorders. Therefore, understanding the intricate mechanisms of positive and negative regulation of protein neddylation is crucial for developing therapeutic interventions targeting this essential biological process.'
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Proteins (1)

Compounds (2)