The enzymes of the NEDDylation pathway play a pivotal role in the activation of the largest class of ubiquitin E3 ligases called Cullin-RING-Ligases (CRLs). Akin to ubiquitylation three classes of enzymes are involved in the process of mammalian NEDDylation; E1 activating enzyme (APP-BP1/ UBA3 heterodimer), E2 conjugating enzymes (UBE2M or UBE2F) and E3 ligases the defective in Cul neddylation 1 domain-containing proteins (DCUN1D1-5) (Meyer-Schaller et al., 2009; Huang et al., 2011). There are 5 human DCUN1D1-5 proteins are also named defective in Cul neddylation 1 like proteins (DCNL1–5) (Meyer-Schaller et al., 2009). Cloning of DCNL2 was first described by Kurz et al. (2005) and Lamesch et al. (2007). The DCNLs have distinct amino-terminal domains, but share a conserved C-terminal potentiating neddylation (PONY) domain (Kurz et al., 2008). It has been determined that the interaction between the DCNLs and Cul1 occurs through the PONY domain and the Winged Helix DNA binding domain (WHB) respectively (Kurz et al., 2008; Scott et al., 2011). Pairwise analysis of 30 combinations of the five DCNLPONY domains and six cullin WHB subdomains by isothermal titration calorimetry have all shown interaction albeit with differing affinities (Monda et al., 2013).
Huang G, Kaufman A J, Ramanathan Y, Singh B (2011) SCCRO (DCUN1D1) promotes nuclear translocation and assembly of the neddylation E3 complex, J Biol Chem 286, 10297-10304.
Kurz T, Chou YC, Willems AR, Meyer-Schaller N, Hecht ML, Tyers M, Peter M, Sicheri F. (2008) Dcn1 functions as a scaffold-type E3 ligase for cullin neddylation, Mol Cell 29, 23-35.
Kurz T, Ozlü N, Rudolf F, O'Rourke SM, Luke B, Hofmann K, Hyman AA, Bowerman B, Peter M. (2005) The conserved protein DCN-1/Dcn1p is required for cullin neddylation in C. elegans and S. cerevisiae, Nature 435, 1257-1261.
Lamesch P, Li N, Milstein S, Fan C, Hao T, Szabo G, Hu Z, Venkatesan K, Bethel G, Martin P, Rogers J, Lawlor S, McLaren S, Dricot A, Borick H, Cusick ME, Vandenhaute J, Dunham I, Hill DE,Vidal M. (2007) hORFeome v3.1: a resource of human open reading frames representing over 10,000 human genes,Genomics 89, 307-315.
Meyer-Schaller N, Chou YC, Sumara I, Martin DD, Kurz T, Katheder N, Hofmann K, Berthiaume LG, Sicheri F, Peter M. (2009) The human Dcn1-like protein DCNL3 promotes Cul3 neddylation at membranes, Proc Natl Acad Sci U S A 106, 12365-12370.
Monda J.K,Scott DC, Miller DJ, Lydeard J, King D, Harper JW, Bennett EJ, Schulman BA. (2013) Structural Conservation of Distinctive N-terminal Acetylation-Dependent Interactions across a Family of Mammalian NEDD8 Ligation Enzymes, Structure 21, 42-53.
Scott D.C, Monda JK, Bennett EJ, Harper JW, Schulman B.A. (2011) N-terminal acetylation acts as an avidity enhancer within an interconnected multiprotein complex, Science 334, 674-678.