3b08
Crystal structure of the mouse HOIL1-L-NZF in complex with linear di-ubiquitin
Structural highlights
FunctionHOIL1_MOUSE 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 ('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 (By similarity). Publication Abstract from PubMedThe linear ubiquitin chain assembly complex (LUBAC) is a key nuclear factor-kappaB (NF-kappaB) pathway component that produces linear polyubiquitin chains. The HOIL-1L subunit of LUBAC has been shown to bind linear chains; however, detailed structural and functional analyses on the binding between LUBAC and linear chains have not been performed. In this study, we found that the Npl4 zinc finger (NZF) domain of HOIL-1L specifically binds linear polyubiquitin chains and determined the crystal structure of the HOIL-1L NZF domain in complex with linear diubiquitin at 1.7-A resolution. The HOIL-1L NZF domain consists of a zinc-coordinating "NZF core" region and an additional alpha-helical "NZF tail" region. The HOIL-1L NZF core binds both the canonical Ile44-centered hydrophobic surface on the distal ubiquitin and a Phe4-centered hydrophobic patch on the proximal ubiquitin, representing a mechanism for the specific recognition of linear chains. The NZF tail binds the proximal ubiquitin to enhance the binding affinity. These recognition mechanisms were supported by the accompanying in vitro and in vivo structure-based mutagenesis experiments. Specific recognition of linear ubiquitin chains by the Npl4 zinc finger (NZF) domain of the HOIL-1L subunit of the linear ubiquitin chain assembly complex.,Sato Y, Fujita H, Yoshikawa A, Yamashita M, Yamagata A, Kaiser SE, Iwai K, Fukai S Proc Natl Acad Sci U S A. 2011 Dec 20;108(51):20520-5. Epub 2011 Dec 2. PMID:22139374[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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