Background
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). 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). CRL subunits include, a scaffold protein (cullin family protein), a Ring finger protein either Rbx1 (Cul1-4) or Rbx2 (Cul5) that binds a ubiquitin-loaded E2 Ube2M or Ube2F respectively (Sarikas, et al., 2011; Skowyra, et al., 1997). Many CRL E3 ligases have additional linker proteins; such as Skp1 associated with Cul1 and DDB1 associated with Cul4. The first CRL E3 ligase identified was named Skp1/Cullin or Cdc53/F-box (SCF) from Saccharomyces cerevisiae. CRLs function through their cognate substrate-recognition molecules, such as the F-box proteins SOCS, BTB and DCAF; each of these contain a distinct motif that is recognized by an adaptor molecule which is itself linked to a cognate cullin. There are approximately 61 human F-box proteins all of which can bind to Skp1 through the F-box domain. It is thought most of the F-box proteins can be assembled into the SCF E3 complex through Skp1, which binds to CUL1 (Sarikas et al., 2011).
References
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.
Kipreos ET, Lander LE, Wing JP, He WW, Hedgecock E.M. (1996) cul-1 is required for cell cycle exit in C. elegans and identifies a novel gene family, Cell 85, 829-839.
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.
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.
Sarikas, A., Hartmann, T. and Pan, Z.Q. (2011) The cullin protein family, Genome biology 12, 220.
Skowyra D, Craig KL, Tyers M, Elledge SJ, Harper J.W. (1997) F-box proteins are receptors that recruit phosphorylated substrates to the SCF ubiquitin-ligase complex, Cell 91, 209-219.