5h7s

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]} [UBE2N_HUMAN] The UBE2V1-UBE2N and UBE2V2-UBE2N heterodimers catalyze the synthesis of non-canonical 'Lys-63'-linked polyubiquitin chains. This type of polyubiquitination does not lead to protein degradation by the proteasome. Mediates transcriptional activation of target genes. Plays a role in the control of progress through the cell cycle and differentiation. Plays a role in the error-free DNA repair pathway and contributes to the survival of cells after DNA damage. Acts together with the E3 ligases, HLTF and SHPRH, in the 'Lys-63'-linked poly-ubiquitination of PCNA upon genotoxic stress, which is required for DNA repair. Appears to act together with E3 ligase RNF5 in the 'Lys-63'-linked polyubiquitination of JKAMP thereby regulating JKAMP function by decreasing its association with components of the proteasome and ERAD. Promotes TRIM5 capsid-specific restriction activity and the UBE2V1-UBE2N heterodimer acts in concert with TRIM5 to generate 'Lys-63'-linked polyubiquitin chains which activate the MAP3K7/TAK1 complex which in turn results in the induction and expression of NF-kappa-B and MAPK-responsive inflammatory genes (By similarity).^{[3] [4] [5] [6] [7]} [LNX1_HUMAN] E3 ubiquitin-protein ligase that mediates ubiquitination and subsequent proteasomal degradation of NUMB. E3 ubiquitin ligases accept ubiquitin from an E2 ubiquitin-conjugating enzyme in the form of a thioester and then directly transfers the ubiquitin to targeted substrates. Mediates ubiquitination of isoform p66 and isoform p72 of NUMB, but not that of isoform p71 or isoform p65 (By similarity). Isoform 2 provides an endocytic scaffold for IGSF5/JAM4 (By similarity).

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. ↑ Hofmann RM, Pickart CM. Noncanonical MMS2-encoded ubiquitin-conjugating enzyme functions in assembly of novel polyubiquitin chains for DNA repair. Cell. 1999 Mar 5;96(5):645-53. PMID:10089880
4. ↑ Bothos J, Summers MK, Venere M, Scolnick DM, Halazonetis TD. The Chfr mitotic checkpoint protein functions with Ubc13-Mms2 to form Lys63-linked polyubiquitin chains. Oncogene. 2003 Oct 16;22(46):7101-7. PMID:14562038 doi:10.1038/sj.onc.1206831
5. ↑ Tcherpakov M, Delaunay A, Toth J, Kadoya T, Petroski MD, Ronai ZA. Regulation of endoplasmic reticulum-associated degradation by RNF5-dependent ubiquitination of JNK-associated membrane protein (JAMP). J Biol Chem. 2009 May 1;284(18):12099-109. doi: 10.1074/jbc.M808222200. Epub 2009, Mar 6. PMID:19269966 doi:10.1074/jbc.M808222200
6. ↑ 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
7. ↑ Pertel T, Hausmann S, Morger D, Zuger S, Guerra J, Lascano J, Reinhard C, Santoni FA, Uchil PD, Chatel L, Bisiaux A, Albert ML, Strambio-De-Castillia C, Mothes W, Pizzato M, Grutter MG, Luban J. TRIM5 is an innate immune sensor for the retrovirus capsid lattice. Nature. 2011 Apr 21;472(7343):361-5. doi: 10.1038/nature09976. PMID:21512573 doi:10.1038/nature09976