2jo9

Structural highlights

Disease

ITCH_MOUSE Note=Defects in Itch are the cause of the itchy phenotype which is an inflammatory and immunological condition characterized by inflammation in the lung and stomach, hyperplasia in lymphoid and hematopoietic cells and constant itching in the skin.^[1]

Function

ITCH_MOUSE Acts as an E3 ubiquitin-protein ligase which accepts ubiquitin from an E2 ubiquitin-conjugating enzyme in the form of a thioester and then directly transfers the ubiquitin to targeted substrates. It catalyzes 'Lys-29'-, 'Lys-48'- and 'Lys-63'-linked ubiquitin conjugation. It is involved in the control of inflammatory signaling pathways. Is an essential component of a ubiquitin-editing protein complex, comprising also TNFAIP3, TAX1BP1 and RNF11, that ensures the transient nature of inflammatory signaling pathways. Promotes the association of the complex after TNF stimulation. Once the complex is formed, TNFAIP3 deubiquitinates 'Lys-63' polyubiquitin chains on RIPK1 and catalyzes the formation of 'Lys-48'-polyubiquitin chains. This leads to RIPK1 proteasomal degradation and consequently termination of the TNF- or LPS-mediated activation of NFKB1 (By similarity). Ubiquitinates RIPK2 by 'Lys-63'-linked conjugation and influences NOD2-dependent signal transduction pathways (By similarity). Regulates the transcriptional activity of several transcription factors involved in immune response. Critical regulator of T-helper (TH2) cytokine development through its ability to induce JUNB ubiquitination and degradation. Ubiquitinates SNX9 (By similarity). Ubiquitinates CXCR4 and HGS/HRS and regulates sorting of CXCR4 to the degradative pathway (By similarity). It is involved in the negative regulation of MAVS-dependent cellular antiviral responses. Ubiquitinates MAVS through 'Lys-48'-linked conjugation resulting in MAVS proteasomal degradation (By similarity). Involved in the regulation of apoptosis and reactive oxygen species levels through the ubiquitination and proteasomal degradation of TXNIP (By similarity). Mediates the antiapoptotic activity of epidermal growth factor through the ubiquitination and proteasomal degradation of p15 BID. Targets DTX1 for lysosomal degradation and controls NOTCH1 degradation, in the absence of ligand, through 'Lys-29'-linked polyubiquitination (By similarity).^{[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.

See Also

• Ubiquitin protein ligase 3D structures

References

1. ↑ Perry WL, Hustad CM, Swing DA, O'Sullivan TN, Jenkins NA, Copeland NG. The itchy locus encodes a novel ubiquitin protein ligase that is disrupted in a18H mice. Nat Genet. 1998 Feb;18(2):143-6. PMID:9462742 doi:10.1038/ng0298-143
2. ↑ Fang D, Elly C, Gao B, Fang N, Altman Y, Joazeiro C, Hunter T, Copeland N, Jenkins N, Liu YC. Dysregulation of T lymphocyte function in itchy mice: a role for Itch in TH2 differentiation. Nat Immunol. 2002 Mar;3(3):281-7. Epub 2002 Feb 4. PMID:11828324 doi:10.1038/ni763
3. ↑ Gao M, Labuda T, Xia Y, Gallagher E, Fang D, Liu YC, Karin M. Jun turnover is controlled through JNK-dependent phosphorylation of the E3 ligase Itch. Science. 2004 Oct 8;306(5694):271-5. Epub 2004 Sep 9. PMID:15358865 doi:10.1126/science.1099414
4. ↑ Oberst A, Malatesta M, Aqeilan RI, Rossi M, Salomoni P, Murillas R, Sharma P, Kuehn MR, Oren M, Croce CM, Bernassola F, Melino G. The Nedd4-binding partner 1 (N4BP1) protein is an inhibitor of the E3 ligase Itch. Proc Natl Acad Sci U S A. 2007 Jul 3;104(27):11280-5. Epub 2007 Jun 25. PMID:17592138 doi:10.1073/pnas.0701773104
5. ↑ Chastagner P, Israel A, Brou C. AIP4/Itch regulates Notch receptor degradation in the absence of ligand. PLoS One. 2008 Jul 16;3(7):e2735. doi: 10.1371/journal.pone.0002735. PMID:18628966 doi:10.1371/journal.pone.0002735
6. ↑ Azakir BA, Desrochers G, Angers A. The ubiquitin ligase Itch mediates the antiapoptotic activity of epidermal growth factor by promoting the ubiquitylation and degradation of the truncated C-terminal portion of Bid. FEBS J. 2010 Mar;277(5):1319-30. doi: 10.1111/j.1742-4658.2010.07562.x. PMID:20392206 doi:10.1111/j.1742-4658.2010.07562.x
7. ↑ Morales B, Ramirez-Espain X, Shaw AZ, Martin-Malpartida P, Yraola F, Sanchez-Tillo E, Farrera C, Celada A, Royo M, Macias MJ. NMR structural studies of the ItchWW3 domain reveal that phosphorylation at T30 inhibits the interaction with PPxY-containing ligands. Structure. 2007 Apr;15(4):473-83. PMID:17437719 doi:10.1016/j.str.2007.03.005