5dfl

Structural highlights

Function

[UBB_HUMAN] Ubiquitin exists either covalently attached to another protein, or free (unanchored). When covalently bound, it is conjugated to target proteins via an isopeptide bond either as a monomer (monoubiquitin), a polymer linked via different Lys residues of the ubiquitin (polyubiquitin chains) or a linear polymer linked via the initiator Met of the ubiquitin (linear polyubiquitin chains). Polyubiquitin chains, when attached to a target protein, have different functions depending on the Lys residue of the ubiquitin that is linked: Lys-6-linked may be involved in DNA repair; Lys-11-linked is involved in ERAD (endoplasmic reticulum-associated degradation) and in cell-cycle regulation; Lys-29-linked is involved in lysosomal degradation; Lys-33-linked is involved in kinase modification; Lys-48-linked is involved in protein degradation via the proteasome; Lys-63-linked is involved in endocytosis, DNA-damage responses as well as in signaling processes leading to activation of the transcription factor NF-kappa-B. Linear polymer chains formed via attachment by the initiator Met lead to cell signaling. Ubiquitin is usually conjugated to Lys residues of target proteins, however, in rare cases, conjugation to Cys or Ser residues has been observed. When polyubiquitin is free (unanchored-polyubiquitin), it also has distinct roles, such as in activation of protein kinases, and in signaling.^{[1] [2]} [UBE2K_HUMAN] Accepts ubiquitin from the E1 complex and catalyzes its covalent attachment to other proteins. In vitro, in the presence or in the absence of BRCA1-BARD1 E3 ubiquitin-protein ligase complex, catalyzes the synthesis of 'Lys-48'-linked polyubiquitin chains. Does not transfer ubiquitin directly to but elongates monoubiquitinated substrate protein. Mediates the selective degradation of short-lived and abnormal proteins, such as the endoplasmic reticulum-associated degradation (ERAD) of misfolded lumenal proteins. Ubiquitinates huntingtin. May mediate foam cell formation by the suppression of apoptosis of lipid-bearing macrophages through ubiquitination and subsequence degradation of p53/TP53. Proposed to be involved in ubiquitination and proteolytic processing of NF-kappa-B; in vitro supports ubiquitination of NFKB1. In case of infection by cytomegaloviruses may be involved in the US11-dependent degradation of MHC class I heavy chains following their export from the ER to the cytosol. In case of viral infections may be involved in the HPV E7 protein-dependent degradation of RB1.^{[3] [4] [5] [6] [7] [8] [9] [10]}

See Also

• Ubiquitin
• Ubiquitin conjugating enzyme

References

1. ↑ Huang F, Kirkpatrick D, Jiang X, Gygi S, Sorkin A. Differential regulation of EGF receptor internalization and degradation by multiubiquitination within the kinase domain. Mol Cell. 2006 Mar 17;21(6):737-48. PMID:16543144 doi:S1097-2765(06)00120-1
2. ↑ Komander D. The emerging complexity of protein ubiquitination. Biochem Soc Trans. 2009 Oct;37(Pt 5):937-53. doi: 10.1042/BST0370937. PMID:19754430 doi:10.1042/BST0370937
3. ↑ Kalchman MA, Graham RK, Xia G, Koide HB, Hodgson JG, Graham KC, Goldberg YP, Gietz RD, Pickart CM, Hayden MR. Huntingtin is ubiquitinated and interacts with a specific ubiquitin-conjugating enzyme. J Biol Chem. 1996 Aug 9;271(32):19385-94. PMID:8702625
4. ↑ Kikuchi J, Furukawa Y, Kubo N, Tokura A, Hayashi N, Nakamura M, Matsuda M, Sakurabayashi I. Induction of ubiquitin-conjugating enzyme by aggregated low density lipoprotein in human macrophages and its implications for atherosclerosis. Arterioscler Thromb Vasc Biol. 2000 Jan;20(1):128-34. PMID:10634809
5. ↑ Furukawa Y, Kubo N, Kikuchi J, Tokura A, Fujita N, Sakurabayashi I. Regulation of macrophage-specific gene expression by degenerated lipoproteins. Electrophoresis. 2000 Jan;21(2):338-46. PMID:10675012 doi:<338::AID-ELPS338>3.0.CO;2-9 http://dx.doi.org/10.1002/(SICI)1522-2683(20000101)21:2<338::AID-ELPS338>3.0.CO;2-9
6. ↑ Yamada M, Ohnishi J, Ohkawara B, Iemura S, Satoh K, Hyodo-Miura J, Kawachi K, Natsume T, Shibuya H. NARF, an nemo-like kinase (NLK)-associated ring finger protein regulates the ubiquitylation and degradation of T cell factor/lymphoid enhancer factor (TCF/LEF). J Biol Chem. 2006 Jul 28;281(30):20749-60. Epub 2006 May 19. PMID:16714285 doi:http://dx.doi.org/10.1074/jbc.M602089200
7. ↑ Flierman D, Coleman CS, Pickart CM, Rapoport TA, Chau V. E2-25K mediates US11-triggered retro-translocation of MHC class I heavy chains in a permeabilized cell system. Proc Natl Acad Sci U S A. 2006 Aug 1;103(31):11589-94. Epub 2006 Jul 25. PMID:16868077 doi:http://dx.doi.org/0605215103
8. ↑ Christensen DE, Brzovic PS, Klevit RE. E2-BRCA1 RING interactions dictate synthesis of mono- or specific polyubiquitin chain linkages. Nat Struct Mol Biol. 2007 Oct;14(10):941-8. Epub 2007 Sep 16. PMID:17873885 doi:http://dx.doi.org/10.1038/nsmb1295
9. ↑ David Y, Ziv T, Admon A, Navon A. The E2 ubiquitin conjugating enzymes direct polyubiquitination to preferred lysines. J Biol Chem. 2010 Jan 8. PMID:20061386 doi:M109.089003
10. ↑ Oh KJ, Kalinina A, Bagchi S. Destabilization of Rb by human papillomavirus E7 is cell cycle dependent: E2-25K is involved in the proteolysis. Virology. 2010 Jan 5;396(1):118-24. doi: 10.1016/j.virol.2009.10.018. Epub 2009, Nov 10. PMID:19906396 doi:http://dx.doi.org/10.1016/j.virol.2009.10.018
11. ↑ Middleton AJ, Day CL. The molecular basis of lysine 48 ubiquitin chain synthesis by Ube2K. Sci Rep. 2015 Nov 23;5:16793. doi: 10.1038/srep16793. PMID:26592444 doi:http://dx.doi.org/10.1038/srep16793