NEDD8adenylate

NEDD8adenylate is a molecular intermediate in the neddylation pathway. Neddylation is a post-translational modification process that involves the covalent attachment of the NEDD8 protein (Neural precursor cell expressed, developmentally down-regulated gene 8) to target proteins. This process is functionally analogous to ubiquitination but involves a distinct ubiquitin-like modifier.

The formation of NEDD8adenylate is a crucial early step catalyzed by the NEDD8-activating enzyme (NAE). NAE possesses E1 enzymatic activity, meaning it is responsible for activating NEDD8. In this activation process, NAE uses ATP to adenylate the C-terminus of NEDD8, forming a high-energy thioester intermediate. This NEDD8adenylate intermediate is then transferred to a NEDD8 conjugating enzyme (a UBC12 homolog), forming a NEDD8-ubiquitin carrier protein intermediate. This intermediate then transfers NEDD8 to a substrate protein, completing the neddylation process.

The NEDD8adenylate intermediate is transient and highly reactive, facilitating the subsequent transfer of NEDD8. The neddylation pathway targets a variety of proteins, including cullins, which are essential components of cullin-RING ligase (CRL) E3 ubiquitin ligase complexes. Neddylation of cullins is critical for the proper assembly and function of CRLs, which play significant roles in regulating protein degradation, cell cycle progression, DNA repair, and signal transduction. Dysregulation of neddylation is implicated in various cellular processes and diseases, making the study of intermediates like NEDD8adenylate important for understanding cellular regulation and potential therapeutic interventions.

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