| Structural highlights
Disease
[ITCH_HUMAN] Defects in ITCH are the cause of syndromic multisystem autoimmune disease (SMAD) [MIM:613385]. SMAD is characterized by organomegaly, failure to thrive, developmental delay, dysmorphic features and autoimmune inflammatory cell infiltration of the lungs, liver and gut.[1]
Function
[ARHG7_RAT] Acts as a RAC1 guanine nucleotide exchange factor (GEF) and can induce membrane ruffling. Functions in cell migration, attachment and cell spreading. Promotes targeting of RAC1 to focal adhesions. May function as a positive regulator of apoptosis. Downstream of NMDA receptors and CaMKK-CaMK1 signaling cascade, promotes the formation of spines and synapses in hippocampal neurons (By similarity). [ITCH_HUMAN] 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. Ubiquitinates RIPK2 by 'Lys-63'-linked conjugation and influences NOD2-dependent signal transduction pathways. Regulates the transcriptional activity of several transcription factors, and probably plays an important role in the regulation of immune response. Ubiquitinates NFE2 by 'Lys-63' linkages and is implicated in the control of the development of hematopoietic lineages. Critical regulator of T-helper (TH2) cytokine development through its ability to induce JUNB ubiquitination and degradation (By similarity). Ubiquitinates SNX9. Ubiquitinates CXCR4 and HGS/HRS and regulates sorting of CXCR4 to the degradative pathway. 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. Involved in the regulation of apoptosis and reactive oxygen species levels through the ubiquitination and proteasomal degradation of TXNIP. 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.[2] [3] [4] [5] [6] [7] [8] [9] [10] [11] [12]
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
Cross-talk between G protein-coupled receptors and receptor tyrosine kinase signaling pathways is crucial to the efficient relay and integration of cellular information. Here we identify and define the novel binding interaction of the E3 ubiquitin ligase atrophin-interacting protein 4 (AIP4) with the GTP exchange factor beta-p21-activated kinase-interactive exchange factor (beta PIX). We demonstrate that this interaction is mediated in part by the beta PIX-SH3 domain binding to a proline-rich stretch of AIP4. Analysis of the interaction by isothermal calorimetry is consistent with a heterotrimeric complex with one AIP4-derived peptide binding to two beta PIX-SH3 domains. We determined the crystal structure of the beta PIX-SH3.AIP4 complex to 2.0-A resolution. In contrast to the calorimetry results, the crystal structure shows a monomeric complex in which AIP4 peptide binds the beta PIX-SH3 domain as a canonical Class I ligand with an additional type II polyproline helix that makes extensive contacts with another face of beta PIX. Taken together, the novel interaction between AIP4 and beta PIX represents a new regulatory node for G protein-coupled receptor and receptor tyrosine kinase signal integration. Our structure of the beta PIX-SH3.AIP4 complex provides important insight into the mechanistic basis for beta PIX scaffolding of signaling components, especially those involved in cross-talk.
A novel interaction between atrophin-interacting protein 4 and beta-p21-activated kinase-interactive exchange factor is mediated by an SH3 domain.,Janz JM, Sakmar TP, Min KC J Biol Chem. 2007 Sep 28;282(39):28893-903. Epub 2007 Jul 25. PMID:17652093[13]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Lohr NJ, Molleston JP, Strauss KA, Torres-Martinez W, Sherman EA, Squires RH, Rider NL, Chikwava KR, Cummings OW, Morton DH, Puffenberger EG. Human ITCH E3 ubiquitin ligase deficiency causes syndromic multisystem autoimmune disease. Am J Hum Genet. 2010 Mar 12;86(3):447-53. doi: 10.1016/j.ajhg.2010.01.028. Epub, 2010 Feb 18. PMID:20170897 doi:10.1016/j.ajhg.2010.01.028
- ↑ Marchese A, Raiborg C, Santini F, Keen JH, Stenmark H, Benovic JL. The E3 ubiquitin ligase AIP4 mediates ubiquitination and sorting of the G protein-coupled receptor CXCR4. Dev Cell. 2003 Nov;5(5):709-22. PMID:14602072
- ↑ Chastagner P, Israel A, Brou C. Itch/AIP4 mediates Deltex degradation through the formation of K29-linked polyubiquitin chains. EMBO Rep. 2006 Nov;7(11):1147-53. Epub 2006 Oct 6. PMID:17028573 doi:10.1038/sj.embor.7400822
- ↑ Yang C, Zhou W, Jeon MS, Demydenko D, Harada Y, Zhou H, Liu YC. Negative regulation of the E3 ubiquitin ligase itch via Fyn-mediated tyrosine phosphorylation. Mol Cell. 2006 Jan 6;21(1):135-41. PMID:16387660 doi:10.1016/j.molcel.2005.11.014
- ↑ Lee TL, Shyu YC, Hsu TY, Shen CK. Itch regulates p45/NF-E2 in vivo by Lys63-linked ubiquitination. Biochem Biophys Res Commun. 2008 Oct 24;375(3):326-30. doi:, 10.1016/j.bbrc.2008.07.164. Epub 2008 Aug 19. PMID:18718448 doi:10.1016/j.bbrc.2008.07.164
- ↑ Scialpi F, Malatesta M, Peschiaroli A, Rossi M, Melino G, Bernassola F. Itch self-polyubiquitylation occurs through lysine-63 linkages. Biochem Pharmacol. 2008 Dec 1;76(11):1515-21. doi: 10.1016/j.bcp.2008.07.028., Epub 2008 Jul 31. PMID:18718449 doi:10.1016/j.bcp.2008.07.028
- ↑ 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
- ↑ Tao M, Scacheri PC, Marinis JM, Harhaj EW, Matesic LE, Abbott DW. ITCH K63-ubiquitinates the NOD2 binding protein, RIP2, to influence inflammatory signaling pathways. Curr Biol. 2009 Aug 11;19(15):1255-63. doi: 10.1016/j.cub.2009.06.038. Epub 2009 , Jul 9. PMID:19592251 doi:10.1016/j.cub.2009.06.038
- ↑ Shembade N, Parvatiyar K, Harhaj NS, Harhaj EW. The ubiquitin-editing enzyme A20 requires RNF11 to downregulate NF-kappaB signalling. EMBO J. 2009 Mar 4;28(5):513-22. doi: 10.1038/emboj.2008.285. Epub 2009 Jan 8. PMID:19131965 doi:10.1038/emboj.2008.285
- ↑ You F, Sun H, Zhou X, Sun W, Liang S, Zhai Z, Jiang Z. PCBP2 mediates degradation of the adaptor MAVS via the HECT ubiquitin ligase AIP4. Nat Immunol. 2009 Dec;10(12):1300-8. doi: 10.1038/ni.1815. Epub 2009 Nov 1. PMID:19881509 doi:10.1038/ni.1815
- ↑ 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
- ↑ Zhang P, Wang C, Gao K, Wang D, Mao J, An J, Xu C, Wu D, Yu H, Liu JO, Yu L. The ubiquitin ligase itch regulates apoptosis by targeting thioredoxin-interacting protein for ubiquitin-dependent degradation. J Biol Chem. 2010 Mar 19;285(12):8869-79. doi: 10.1074/jbc.M109.063321. Epub 2010, Jan 12. PMID:20068034 doi:10.1074/jbc.M109.063321
- ↑ Janz JM, Sakmar TP, Min KC. A novel interaction between atrophin-interacting protein 4 and beta-p21-activated kinase-interactive exchange factor is mediated by an SH3 domain. J Biol Chem. 2007 Sep 28;282(39):28893-903. Epub 2007 Jul 25. PMID:17652093 doi:http://dx.doi.org/10.1074/jbc.M702678200
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