| Structural highlights
Function
RNF31_HUMAN E3 ubiquitin-protein ligase component of the LUBAC complex which conjugates linear ('M-1'-linked) polyubiquitin chains to substrates and plays a key role in NF-kappa-B activation and regulation of inflammation. LUBAC conjugates linear polyubiquitin to IKBKG and RIPK1 and is involved in activation of the canonical NF-kappa-B and the JNK signaling pathways. Linear ubiquitination mediated by the LUBAC complex interferes with TNF-induced cell death and thereby prevents inflammation. LUBAC is proposed to be recruited to the TNF-R1 signaling complex (TNF-RSC) following polyubiquitination of TNF-RSC components by BIRC2 and/or BIRC3 and to conjugate linear polyubiquitin to IKBKG and possibly other components contributing to the stability of the complex. Binds polyubiquitin of different linkage types.[1] [2] [3] [4] [5] [6] [7]
Publication Abstract from PubMed
Protein ubiquitination plays a key role in the regulation of cellular processes, and misregulation of the ubiquitin system is linked to many diseases. So far, development of tool compounds that target enzymes of the ubiquitin system has been slow and only a few specific inhibitors are available. Here, we report the selection of single-domain antibodies (single-dAbs) based on a human scaffold that recognize the catalytic domain of HOIP, a subunit of the multi-component E3 LUBAC and member of the RBR family of E3 ligases. Some of these dAbs affect ligase activity and provide mechanistic insight into the ubiquitin transfer mechanism of different E2-conjugating enzymes. Furthermore, we show that the co-crystal structure of a HOIP RBR/dAb complex serves as a robust platform for soaking of ligands that target the active site cysteine of HOIP, thereby providing easy access to structure-based ligand design for this important class of E3 ligases.
Single-Domain Antibodies as Crystallization Chaperones to Enable Structure-Based Inhibitor Development for RBR E3 Ubiquitin Ligases.,Tsai YI, Johansson H, Dixon D, Martin S, Chung CW, Clarkson J, House D, Rittinger K Cell Chem Biol. 2019 Dec 2. pii: S2451-9456(19)30389-7. doi:, 10.1016/j.chembiol.2019.11.007. PMID:31813847[8]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ Kirisako T, Kamei K, Murata S, Kato M, Fukumoto H, Kanie M, Sano S, Tokunaga F, Tanaka K, Iwai K. A ubiquitin ligase complex assembles linear polyubiquitin chains. EMBO J. 2006 Oct 18;25(20):4877-87. Epub 2006 Sep 28. PMID:17006537 doi:10.1038/sj.emboj.7601360
- ↑ Haas TL, Emmerich CH, Gerlach B, Schmukle AC, Cordier SM, Rieser E, Feltham R, Vince J, Warnken U, Wenger T, Koschny R, Komander D, Silke J, Walczak H. Recruitment of the linear ubiquitin chain assembly complex stabilizes the TNF-R1 signaling complex and is required for TNF-mediated gene induction. Mol Cell. 2009 Dec 11;36(5):831-44. doi: 10.1016/j.molcel.2009.10.013. PMID:20005846 doi:10.1016/j.molcel.2009.10.013
- ↑ Tokunaga F, Sakata S, Saeki Y, Satomi Y, Kirisako T, Kamei K, Nakagawa T, Kato M, Murata S, Yamaoka S, Yamamoto M, Akira S, Takao T, Tanaka K, Iwai K. Involvement of linear polyubiquitylation of NEMO in NF-kappaB activation. Nat Cell Biol. 2009 Feb;11(2):123-32. doi: 10.1038/ncb1821. Epub 2009 Jan 11. PMID:19136968 doi:10.1038/ncb1821
- ↑ Gerlach B, Cordier SM, Schmukle AC, Emmerich CH, Rieser E, Haas TL, Webb AI, Rickard JA, Anderton H, Wong WW, Nachbur U, Gangoda L, Warnken U, Purcell AW, Silke J, Walczak H. Linear ubiquitination prevents inflammation and regulates immune signalling. Nature. 2011 Mar 31;471(7340):591-6. doi: 10.1038/nature09816. PMID:21455173 doi:10.1038/nature09816
- ↑ Tokunaga F, Nakagawa T, Nakahara M, Saeki Y, Taniguchi M, Sakata S, Tanaka K, Nakano H, Iwai K. SHARPIN is a component of the NF-kappaB-activating linear ubiquitin chain assembly complex. Nature. 2011 Mar 31;471(7340):633-6. doi: 10.1038/nature09815. PMID:21455180 doi:10.1038/nature09815
- ↑ Ikeda F, Deribe YL, Skanland SS, Stieglitz B, Grabbe C, Franz-Wachtel M, van Wijk SJ, Goswami P, Nagy V, Terzic J, Tokunaga F, Androulidaki A, Nakagawa T, Pasparakis M, Iwai K, Sundberg JP, Schaefer L, Rittinger K, Macek B, Dikic I. SHARPIN forms a linear ubiquitin ligase complex regulating NF-kappaB activity and apoptosis. Nature. 2011 Mar 31;471(7340):637-41. doi: 10.1038/nature09814. PMID:21455181 doi:10.1038/nature09814
- ↑ Smit JJ, Monteferrario D, Noordermeer SM, van Dijk WJ, van der Reijden BA, Sixma TK. The E3 ligase HOIP specifies linear ubiquitin chain assembly through its RING-IBR-RING domain and the unique LDD extension. EMBO J. 2012 Oct 3;31(19):3833-44. doi: 10.1038/emboj.2012.217. Epub 2012 Aug 3. PMID:22863777 doi:10.1038/emboj.2012.217
- ↑ Tsai YI, Johansson H, Dixon D, Martin S, Chung CW, Clarkson J, House D, Rittinger K. Single-Domain Antibodies as Crystallization Chaperones to Enable Structure-Based Inhibitor Development for RBR E3 Ubiquitin Ligases. Cell Chem Biol. 2019 Dec 2. pii: S2451-9456(19)30389-7. doi:, 10.1016/j.chembiol.2019.11.007. PMID:31813847 doi:http://dx.doi.org/10.1016/j.chembiol.2019.11.007
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