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  • A growing number of other post translational modifications


    A growing number of other post-translational modifications are implicated in regulation of the ubiquitin system, including substrate modification by hydroxylation, glycosylation, acetylation, methylation, modification by poly(ADP-ribose) (PAR), and attachment of ubiquitin-like modifiers. The HIF1-α and HIF2-α transcription factors undergo proline hydroxylation in response to increased oxygen levels and become substrates for the multi-subunit RING E3, CRL2VHL. The hydroxylation reaction is mediated by proline-hydroxylase domain (PHD) proteins, which are themselves targets for SIAH RING E3s. SIAH Fmoc-D-Phe(4-Cl)-OH is positively regulated by HIF transcriptionally, creating a positive feedback loop to increase HIF1-α levels [5]. A subfamily of F-box proteins, denoted as Fbs1–5, has the potential to recognize glycosylated proteins in the cytosol, which have presumably been transported out of the endoplasmic reticulum (ER). This provides a means to target these displaced glycoproteins for ubiquitination and proteasomal degradation [60]. Modification of proteins with the small ubiquitin-like modifier (SUMO) family of proteins can inhibit substrate degradation by competing for specific sites of ubiquitination or by altering the localization of modified proteins. Perhaps a more general role for sumoylation is to target proteins for ubiquitination, particularly those modified with chains of SUMO (in metazoans SUMO 2/3). This occurs by SUMO-targeted ubiquitin ligases (STUbLs), which contain multiple SUMO-interacting motifs (SIMs) in addition to their E3 ligase domains [61]. The RING E3 RNF146 uses a WWE domain to recognize substrates modified with poly(ADP-ribose) (PAR). In response to Wnt signaling, axin is PARsylated by tankyrase and subsequently ubiquitinated by RNF146, ultimately resulting in its proteasomal degradation. In vitro, PAR as been shown to stimulate the ligase activity of RNF146, though the mechanism is presently unknown [62], [63], [64]. There are other RING-type E3s that contain WWE domains, including the Deltex family, whose members play an important role in Notch signaling. Thus, it is likely that additional examples of regulation by PARsylation will emerge in the future. There is a complex dynamic between ubiquitination, acetylation, and methylation of lysines as part of the histone code [65]. Additionally, there is data to suggest that specific lysines in p53 that are targets of Mdm2–MdmX are also acetylated, thereby preventing their ubiquitination [66]. The acetylation of Mdm2 itself may decrease its activity towards p53 [67]. There is also evidence for interplay between acetylation and ubiquitination of transcription factors such as estrogen receptor-α [68]. Finally, for E3s to target substrates they must exist in the same cellular compartment. Some RING-type E3s have nuclear localization signals and many RING-type E3s are transmembrane proteins targeted to sites such as the ER, plasma membrane, endosomes, peroxisomes, and mitochondria [42], [69], [70], [71], [72], [73].
    RING-type domain structure RING structure is conformed as a consequence of a cross-braced arrangement of eight Zn coordinating residues, generally Cys and His, with conserved spacing between these residues (Fig. 2B and C). Canonical RINGs have either one or two His in the linear arrangement of coordinating residues, denoted C3H2C3 or C3HC4, however other variations exist. The PHD/LAP finger found in the transcription factor NF-X1 and the MARCH family of membrane-bound E3s is defined by its C4HC3 consensus. RINGs having a C8 configuration (CNOT4) or an Asp residue in the final position (e.g. Rbx1 and TRAF6) have been shown to have ligase activity [74], [75], [76]. Thus, it has become apparent that categorizing RINGs by the linear arrangement of coordinating residues has little to do with functional properties of the domain. Nevertheless, context does matter, as swapping Zn liganding residues in a C3H2C3 RING to create a C3HC4 configuration resulted in loss of activity for AO7 (RNF25), one of the first RING E3s studied [50]. NF-X1 contains a sequence in which both a RING and a PHD/LAP motif are recognizable, but only the PHD/LAP consensus is functional [77]. Unlike RING domain E3s, U-box proteins do not coordinate Zn but adopt a RING-like tertiary structure for binding E2, stabilized by non-covalent interactions among core amino acids [16]. Additionally, some pathogenic bacteria have evolved proteins that show no sequence homology to eukaryotic RING or U-box domains, yet fold into highly similar structures and display robust ubiquitin ligase activity [78], [79].