3dqv

Structural highlights

Function

[NEDD8_HUMAN] Ubiquitin-like protein which plays an important role in cell cycle control and embryogenesis. Covalent attachment to its substrates requires prior activation by the E1 complex UBE1C-APPBP1 and linkage to the E2 enzyme UBE2M. Attachment of NEDD8 to cullins activates their associated E3 ubiquitin ligase activity, and thus promotes polyubiquitination and proteasomal degradation of cyclins and other regulatory proteins.^{[1] [2] [3]} [RBX1_HUMAN] E3 ubiquitin ligase component of multiple cullin-RING-based E3 ubiquitin-protein ligase complexes which mediate the ubiquitination and subsequent proteasomal degradation of target proteins, including proteins involved in cell cycle progression, signal transduction, transcription and transcription-coupled nucleotide excision repair. The functional specificity of the E3 ubiquitin-protein ligase complexes depends on the variable substrate recognition components. As a component of the CSA complex promotes the ubiquitination of ERCC6 resulting in proteasomal degradation. Through the RING-type zinc finger, seems to recruit the E2 ubiquitination enzyme, like CDC34, to the complex and brings it into close proximity to the substrate. Probably also stimulates CDC34 autoubiquitination. May be required for histone H3 and histone H4 ubiquitination in response to ultraviolet and for subsequent DNA repair. Promotes the neddylation of CUL1, CUL2, CUL4 and CUL4 via its interaction with UBE2M.^{[4] [5] [6] [7] [8]} [CUL5_HUMAN] Core component of multiple SCF-like ECS (Elongin-Cullin 2/5-SOCS-box protein) E3 ubiquitin-protein ligase complexes, which mediate the ubiquitination and subsequent proteasomal degradation of target proteins. As a scaffold protein may contribute to catalysis through positioning of the substrate and the ubiquitin-conjugating enzyme. The functional specificity of the E3 ubiquitin-protein ligase complex depends on the variable substrate recognition component. ECS(SOCS1) seems to direct ubiquitination of JAk2. Seems to be involved poteosomal degradation of p53/TP53 stimulated by adenovirus E1B-55 kDa protein. May form a cell surface vasopressin receptor.

Evolutionary Conservation

Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf.

See Also

• Cullin
• NEDD8
• RING box protein

References

1. ↑ Liakopoulos D, Busgen T, Brychzy A, Jentsch S, Pause A. Conjugation of the ubiquitin-like protein NEDD8 to cullin-2 is linked to von Hippel-Lindau tumor suppressor function. Proc Natl Acad Sci U S A. 1999 May 11;96(10):5510-5. PMID:10318914
2. ↑ Hori T, Osaka F, Chiba T, Miyamoto C, Okabayashi K, Shimbara N, Kato S, Tanaka K. Covalent modification of all members of human cullin family proteins by NEDD8. Oncogene. 1999 Nov 18;18(48):6829-34. PMID:10597293 doi:http://dx.doi.org/10.1038/sj.onc.1203093
3. ↑ Amir RE, Iwai K, Ciechanover A. The NEDD8 pathway is essential for SCF(beta -TrCP)-mediated ubiquitination and processing of the NF-kappa B precursor p105. J Biol Chem. 2002 Jun 28;277(26):23253-9. Epub 2002 Apr 12. PMID:11953428 doi:http://dx.doi.org/10.1074/jbc.M200967200
4. ↑ Kamura T, Conrad MN, Yan Q, Conaway RC, Conaway JW. The Rbx1 subunit of SCF and VHL E3 ubiquitin ligase activates Rub1 modification of cullins Cdc53 and Cul2. Genes Dev. 1999 Nov 15;13(22):2928-33. PMID:10579999
5. ↑ Furukawa M, Zhang Y, McCarville J, Ohta T, Xiong Y. The CUL1 C-terminal sequence and ROC1 are required for efficient nuclear accumulation, NEDD8 modification, and ubiquitin ligase activity of CUL1. Mol Cell Biol. 2000 Nov;20(21):8185-97. PMID:11027288
6. ↑ Groisman R, Kuraoka I, Chevallier O, Gaye N, Magnaldo T, Tanaka K, Kisselev AF, Harel-Bellan A, Nakatani Y. CSA-dependent degradation of CSB by the ubiquitin-proteasome pathway establishes a link between complementation factors of the Cockayne syndrome. Genes Dev. 2006 Jun 1;20(11):1429-34. PMID:16751180 doi:http://dx.doi.org/10.1101/gad.378206
7. ↑ Wang H, Zhai L, Xu J, Joo HY, Jackson S, Erdjument-Bromage H, Tempst P, Xiong Y, Zhang Y. Histone H3 and H4 ubiquitylation by the CUL4-DDB-ROC1 ubiquitin ligase facilitates cellular response to DNA damage. Mol Cell. 2006 May 5;22(3):383-94. PMID:16678110 doi:S1097-2765(06)00230-9
8. ↑ Isobe T, Hattori T, Kitagawa K, Uchida C, Kotake Y, Kosugi I, Oda T, Kitagawa M. Adenovirus E1A inhibits SCF(Fbw7) ubiquitin ligase. J Biol Chem. 2009 Oct 9;284(41):27766-79. Epub 2009 Aug 13. PMID:19679664 doi:M109.006809
9. ↑ Duda DM, Borg LA, Scott DC, Hunt HW, Hammel M, Schulman BA. Structural insights into NEDD8 activation of cullin-RING ligases: conformational control of conjugation. Cell. 2008 Sep 19;134(6):995-1006. PMID:18805092 doi:http://dx.doi.org/10.1016/j.cell.2008.07.022