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). 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). Cul3 expression in human fibroblasts is induced by phorbol 12-myristate 13-acetate (PMA) and suppressed by salicylate (Du et al., 1998). The Cul3/Kelch like 9(KLHL9) /Kelch like 13 (KLHL13) complex is an E3 ligase that controls the behavior of Aurora B on mitotic chromosomes and thereby coordinating mitotic progression and completion of cytokinesis (Sumara et al., 2007). Interaction of Cul3 with Kelch like 7 (KLHL7) leads to the ubiquitylation of the dopamine receptor D4 (DRD4) (Rondou et al., 2008).
References
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