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5ljn

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Structure of the HOIP PUB domain bound to SPATA2 PIM peptide

Structural highlights

5ljn is a 4 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:	X-ray diffraction, Resolution 2.701Å
Ligands:	,
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

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

The linear ubiquitin chain assembly complex (LUBAC) regulates immune signaling, and its function is regulated by the deubiquitinases OTULIN and CYLD, which associate with the catalytic subunit HOIP. However, the mechanism through which CYLD interacts with HOIP is unclear. We here show that CYLD interacts with HOIP via spermatogenesis-associated protein 2 (SPATA2). SPATA2 interacts with CYLD through its non-canonical PUB domain, which binds the catalytic CYLD USP domain in a CYLD B-box-dependent manner. Significantly, SPATA2 binding activates CYLD-mediated hydrolysis of ubiquitin chains. SPATA2 also harbors a conserved PUB-interacting motif that selectively docks into the HOIP PUB domain. In cells, SPATA2 is recruited to the TNF receptor 1 signaling complex and is required for CYLD recruitment. Loss of SPATA2 increases ubiquitination of LUBAC substrates and results in enhanced NOD2 signaling. Our data reveal SPATA2 as a high-affinity binding partner of CYLD and HOIP, and a regulatory component of LUBAC-mediated NF-kappaB signaling.

SPATA2 Links CYLD to LUBAC, Activates CYLD, and Controls LUBAC Signaling.,Elliott PR, Leske D, Hrdinka M, Bagola K, Fiil BK, McLaughlin SH, Wagstaff J, Volkmar N, Christianson JC, Kessler BM, Freund SM, Komander D, Gyrd-Hansen M Mol Cell. 2016 Aug 27. pii: S1097-2765(16)30415-4. doi:, 10.1016/j.molcel.2016.08.001. PMID:27591049^[8]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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
↑ Elliott PR, Leske D, Hrdinka M, Bagola K, Fiil BK, McLaughlin SH, Wagstaff J, Volkmar N, Christianson JC, Kessler BM, Freund SM, Komander D, Gyrd-Hansen M. SPATA2 Links CYLD to LUBAC, Activates CYLD, and Controls LUBAC Signaling. Mol Cell. 2016 Aug 27. pii: S1097-2765(16)30415-4. doi:, 10.1016/j.molcel.2016.08.001. PMID:27591049 doi:http://dx.doi.org/10.1016/j.molcel.2016.08.001