2lgy
Ubiquitin-like domain from HOIL-1
Structural highlights
DiseaseHOIL1_HUMAN Autoinflammatory syndrome with pyogenic bacterial infection and amylopectinosis. FunctionHOIL1_HUMAN E3 ubiquitin-protein ligase, which accepts ubiquitin from specific E2 ubiquitin-conjugating enzymes, such as UBE2L3/UBCM4, and then transfers it to substrates. Functions as an E3 ligase for oxidized IREB2 and both heme and oxygen are necessary for IREB2 ubiquitination. Promotes ubiquitination of TAB2 and IRF3 and their degradation by the proteasome. Component of the LUBAC complex which conjugates linear ('Met-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. Together with FAM105B/otulin, the LUBAC complex regulates the canonical Wnt signaling during angiogenesis. Binds polyubiquitin of different linkage types.[1] [2] [3] [4] [5] [6] [7] [8] [9] Publication Abstract from PubMedThe E3 ligases HOIL-1 and parkin are each comprised of an N-terminal ubiquitin-like (Ubl) domain followed by a zinc-binding region and C-terminal RING-In-between-RING-RING domains. These two proteins, involved in the ubiquitin-mediated degradation pathway, are the only two known E3 ligases to share this type of multidomain architecture. Further, the Ubl domain of both HOIL-1 and parkin has been shown to interact with the S5a subunit of the 26S proteasome. The solution structure of the HOIL-1 Ubl domain was solved using NMR spectroscopy to compare it with that of parkin to determine the structural elements responsible for S5a intermolecular interactions. The final ensemble of 20 structures had a beta-grasp Ubl-fold with an overall backbone RMSD of 0.59 +/- 0.10 A in the structured regions between I55 and L131. HOIL-1 had a unique extension of both beta1 and beta2 sheets compared to parkin and other Ubl domains, a result of a four-residue insertion in this region. A similar 15-residue hydrophobic core in the HOIL-1 Ubl domain resulted in a comparable stability to the parkin Ubl, but significantly lower than that observed for ubiquitin. A comparison with parkin and other Ubl domains indicates that HOIL-1 likely uses a conserved hydrophobic patch (W58, V102, Y127, Y129) found on the beta1 face, the beta3-beta4 loop and beta5, as well as a C-terminal basic residue (R134) to recruit the S5a subunit as part of the ubiquitin-mediated proteolysis pathway. Solution structure of the E3 ligase HOIL-1 Ubl domain.,Beasley SA, Safadi SS, Barber KR, Shaw GS Protein Sci. 2012 Jul;21(7):1085-92. doi: 10.1002/pro.2080. Epub 2012 May 24. PMID:22517668[10] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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