| Structural highlights
Function
[RNF4_HUMAN] E3 ubiquitin-protein ligase which binds polysumoylated chains covalently attached to proteins and mediates 'Lys-6'-, 'Lys-11'-, 'Lys-48'- and 'Lys-63'-linked polyubiquitination of those substrates and their subsequent targeting to the proteasome for degradation. Regulates the degradation of several proteins including PML and the transcriptional activator PEA3. Involved in chromosome alignment and spindle assembly, it regulates the kinetochore CENPH-CENPI-CENPK complex by targeting polysumoylated CENPI to proteasomal degradation. Regulates the cellular responses to hypoxia and heat shock through degradation of respectively EPAS1 and PARP1. Alternatively, it may also bind DNA/nucleosomes and have a more direct role in the regulation of transcription for instance enhancing basal transcription and steroid receptor-mediated transcriptional activation.[1] [2] [3] [4] [5] [6]
Evolutionary Conservation
Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf.
Publication Abstract from PubMed
Mammalian RNF4 is a dimeric RING ubiquitin E3 ligase that ubiquitylates poly-SUMOylated proteins. We found that RNF4 bound ubiquitin-charged UbcH5a tightly but free UbcH5a weakly. To provide insight into the mechanism of RING-mediated ubiquitylation, we docked the UbcH5~ubiquitin thioester onto the RNF4 RING structure. This revealed that with E2 bound to one monomer of RNF4, the thioester-linked ubiquitin could reach across the dimer to engage the other monomer. In this model, the 'Ile44 hydrophobic patch' of ubiquitin is predicted to engage a conserved tyrosine located at the dimer interface of the RING, and mutation of these residues blocked ubiquitylation activity. Thus, dimeric RING ligases are not simply inert scaffolds that bring substrate and E2-loaded ubiquitin into close proximity. Instead, they facilitate ubiquitin transfer by preferentially binding the E2~ubiquitin thioester across the dimer and activating the thioester bond for catalysis.
Mechanism of ubiquitylation by dimeric RING ligase RNF4.,Plechanovova A, Jaffray EG, McMahon SA, Johnson KA, Navratilova I, Naismith JH, Hay RT Nat Struct Mol Biol. 2011 Aug 21;18(9):1052-9. doi: 10.1038/nsmb.2108. PMID:21857666[7]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Kaiser FJ, Moroy T, Chang GT, Horsthemke B, Ludecke HJ. The RING finger protein RNF4, a co-regulator of transcription, interacts with the TRPS1 transcription factor. J Biol Chem. 2003 Oct 3;278(40):38780-5. Epub 2003 Jul 28. PMID:12885770 doi:http://dx.doi.org/10.1074/jbc.M306259200
- ↑ Tatham MH, Geoffroy MC, Shen L, Plechanovova A, Hattersley N, Jaffray EG, Palvimo JJ, Hay RT. RNF4 is a poly-SUMO-specific E3 ubiquitin ligase required for arsenic-induced PML degradation. Nat Cell Biol. 2008 May;10(5):538-46. doi: 10.1038/ncb1716. Epub 2008 Apr 13. PMID:18408734 doi:10.1038/ncb1716
- ↑ Guo B, Sharrocks AD. Extracellular signal-regulated kinase mitogen-activated protein kinase signaling initiates a dynamic interplay between sumoylation and ubiquitination to regulate the activity of the transcriptional activator PEA3. Mol Cell Biol. 2009 Jun;29(11):3204-18. doi: 10.1128/MCB.01128-08. Epub 2009 Mar , 23. PMID:19307308 doi:http://dx.doi.org/10.1128/MCB.01128-08
- ↑ Mukhopadhyay D, Arnaoutov A, Dasso M. The SUMO protease SENP6 is essential for inner kinetochore assembly. J Cell Biol. 2010 Mar 8;188(5):681-92. doi: 10.1083/jcb.200909008. PMID:20212317 doi:http://dx.doi.org/10.1083/jcb.200909008
- ↑ Geoffroy MC, Jaffray EG, Walker KJ, Hay RT. Arsenic-induced SUMO-dependent recruitment of RNF4 into PML nuclear bodies. Mol Biol Cell. 2010 Dec;21(23):4227-39. doi: 10.1091/mbc.E10-05-0449. Epub 2010, Oct 13. PMID:20943951 doi:10.1091/mbc.E10-05-0449
- ↑ van Hagen M, Overmeer RM, Abolvardi SS, Vertegaal AC. RNF4 and VHL regulate the proteasomal degradation of SUMO-conjugated Hypoxia-Inducible Factor-2alpha. Nucleic Acids Res. 2010 Apr;38(6):1922-31. doi: 10.1093/nar/gkp1157. Epub 2009, Dec 21. PMID:20026589 doi:http://dx.doi.org/10.1093/nar/gkp1157
- ↑ Plechanovova A, Jaffray EG, McMahon SA, Johnson KA, Navratilova I, Naismith JH, Hay RT. Mechanism of ubiquitylation by dimeric RING ligase RNF4. Nat Struct Mol Biol. 2011 Aug 21;18(9):1052-9. doi: 10.1038/nsmb.2108. PMID:21857666 doi:10.1038/nsmb.2108
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