Background: NEDD8-activating enzyme (NAE; NEDD8 E1) initiates neddylation, a ubiquitin-like modification that regulates protein stability and signaling. This E1 is a heterodimer of NAE1 (APPBP1) and UBA3. It uses ATP to adenylate NEDD8’s C-terminus, forms a high-energy thioester with UBA3’s catalytic cysteine, then transfers NEDD8 to E2 enzymes UBE2M and UBE2F. These E2s conjugate NEDD8 to cullin scaffolds, activating cullin–RING ligases (CRLs) that ubiquitinate substrates controlling cell cycle, DNA damage responses, hypoxia, and metabolism. The Neddylation inhibitor pevonedistat (MLN4924) targets NAE, suppressing CRL function and inducing cytotoxicity.
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Soucy T.A., et al. (2009) Nature 458(7239):732-736 PMID 19360080
Protein Sequence: SGSMADGEEPEKKRRRIEELLAEKMAVDGGCGDTGDWEGRWNHVKKFLERSGPFTHPDFEPSTESLQFLLDTCKVLVIGAGGLGCELLKNLALSGFRQIHVIDMDTIDVSNLNRQFLFRPKDIGRPKAEVAAEFLNDRVPNCNVVPHFNKIQDFNDTFYRQFHIIVCGLDSIIARRWINGMLISLLNYEDGVLDPSSIVPLIDGGTEGFKGNARVILPGMTACIECTLELYPPQVNFPMCTIASMPRLPEHCIEYVRMLQWPKEQPFGEGVPLDGDDPEHIQWIFQKSLERASQYNIRGVTYRLTQGVVKRIIPAVASTNAVIAAVCATEVFKIATSAYIPLNNYLVFNDVDGLYTYTFEAERKENCPACSQLPQNIQFSPSAKLQEVLDYLTNSASLQMKSPAITATLEGKNRTLYLQSVTSIEERTRPNLSKTLKELGLVDGQELAVADVTTPQTVLFKLHFTS
2 μg NAE1/UBA3 run on 4-12% SDS-PAGE gel under reducing conditions