The enzymes of the ubiquitylation pathway play a pivotal role in a number of cellular processes including the regulated and targeted proteasome dependent degradation of substrate proteins. Three classes of enzymes are involved in the process of ubiquitylation; activating enzymes (E1s), conjugating enzymes (E2s) and protein ligases (E3s). Cullin-RING-Ligases (CRLs) are one largest class of ubiquitin E3 ligases and the enzymes of the NEDDylation pathway play a pivotal role in the activation of these, akin to ubiquitylation, the E1 activating enzyme (APP-BP1/UBA3 heterodimer) and the E2 conjugating enzymes (UBE2M or UBE2F) are involved in mammalian NEDDylation of the Cullin Ring Ligases (CRLs) (Meyer-Schaller et al., 2009; Huang et al., 2011; Morimoto et al., 2003). Identification of the human Cullin1-5 genes were first described by Kipreos et al. (1996). Cullin RING ligases (CRL) comprise the largest subfamily of ubiquitin ligases which are activated by Neddylation. CRLs are involved in cell cycle regulation, DNA replication, DNA damage response (DDR). CRLs contain subunits including, a scaffold protein (cullin family protein), a Ring finger protein either Rbx1 (Cul1-4) or Rbx2 (Cul5) that binds a ubiquitin E2 Ube2M or Ube2F respectively (Sarikas, et al., 2011; Skowyra et al., 1997). Cul-5 has been shown to form a complex with the Ring finger protein Rbx2(Rnf7), the adaptor proteins Elongin B, Elongin C, and the SOCS(suppressors of cytokine signaling) box proteins to form an active CRL-5 E3 ligase (Okumura et al., 2012; Sarikas et al., 2011). Cul-5 also interacts with HSP90 and ErbB2. Cul-5 ubiquitylates ErbB2 - leading to its degradation - in the absence of the traditional adaptors Elongin B/C demonstrating the Elongin B/C independent E3 ligase activity of Cul-5/Rbx2 (Ehrlich et al., 2009).
Ehrlich E.S, Wang T, Luo K, Xiao Z, Niewiadomska AM, Martinez T, Xu W, Neckers L, Yu XF. (2009) Regulation of Hsp90 client proteins by a Cullin5-RING E3 ubiquitin ligase, PNAS 106, 20330-20335.
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.
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, PNAS 106, 12365-12370.
Morimoto M, Nishida T, Nagayama Y, Yasuda H. (2003) Nedd8-modification of Cul1 is promoted by Roc1 as a Nedd8-E3 ligase and regulates its stability, Biochem Biophys Res Commun 301, 392-398.
Okumura F, Matsuzaki M, NakatsukasaK, Kamura T. (2012) The Role of Elongin BC-Containing Ubiquitin Ligases. Front Oncol, 2, 1-13.
Sarikas A, Hartmann, T. and Pan, Z.Q. (2011) The cullin protein family, Genome biology, 12, 220.
Zhou W, Wei, W. and Sun, Y. (2013) Genetically engineered mouse models for functional studies of SKP1-CUL1-F-box-protein (SCF) E3 ubiquitin ligases, Cell Res, 23, 599-619.