title: Specific recognition of linear ubiquitin chains by NEMO is important for NF-kappaB activation.
abstract: Activation of nuclear factor-kappaB (NF-kappaB), a key mediator of inducible transcription in immunity, requires binding of NF-kappaB essential modulator (NEMO) to ubiquitinated substrates. Here, we report that the UBAN (ubiquitin binding in ABIN and NEMO) motif of NEMO selectively binds linear (head-to-tail) ubiquitin chains. Crystal structures of the UBAN motif revealed a parallel coiled-coil dimer that formed a heterotetrameric complex with two linear diubiquitin molecules. The UBAN dimer contacted all four ubiquitin moieties, and the integrity of each binding site was required for efficient NF-kappaB activation. Binding occurred via a surface on the proximal ubiquitin moiety and the canonical Ile44 surface on the distal one, thereby providing specificity for linear chain recognition. Residues of NEMO involved in binding linear ubiquitin chains are required for NF-kappaB activation by TNF-alpha and other agonists, providing an explanation for the detrimental effect of NEMO mutations in patients suffering from X-linked ectodermal dysplasia and immunodeficiency.
authors.affiliation: Structural Biology Research Center, Photon Factory, Institute of Materials Structure Science, High Energy Accelerator Research Organization (KEK), Tsukuba, Ibaraki, Japan.
authors.forename: Simin
authors.initials: S
authors.lastname: Rahighi
authors.forename: Fumiyo
authors.initials: F
authors.lastname: Ikeda
authors.forename: Masato
authors.initials: M
authors.lastname: Kawasaki
authors.forename: Masato
authors.initials: M
authors.lastname: Akutsu
authors.forename: Nobuhiro
authors.initials: N
authors.lastname: Suzuki
authors.forename: Ryuichi
authors.initials: R
authors.lastname: Kato
authors.forename: Tobias
authors.initials: T
authors.lastname: Kensche
authors.forename: Tamami
authors.initials: T
authors.lastname: Uejima
authors.forename: Stuart
authors.initials: S
authors.lastname: Bloor
authors.forename: David
authors.initials: D
authors.lastname: Komander
authors.forename: Felix
authors.initials: F
authors.lastname: Randow
authors.forename: Soichi
authors.initials: S
authors.lastname: Wakatsuki
authors.forename: Ivan
authors.initials: I
authors.lastname: Dikic
mesh_terms: D020816:Amino Acid Motifs; D004476:Ectodermal Dysplasia / Q000378:metabolism; D006801:Humans; D051550:I-kappa B Kinase / Q000737:chemistry / Q000378:metabolism*; D008958:Models, Molecular; D052002:NF-kappa B p50 Subunit / Q000378:metabolism*; D011485:Protein Binding; D025801:Ubiquitin / Q000737:chemistry / Q000378:metabolism*; D014452:Ubiquitins / Q000737:chemistry / Q000378:metabolism; D053632:X-Linked Combined Immunodeficiency Diseases / Q000378:metabolism
chemical_list: C491731:IKBKG protein, human; D052002:NF-kappa B p50 Subunit; C489548:NFKB1 protein, human; C109184:UBD protein, human; D025801:Ubiquitin; D014452:Ubiquitins; D051550:I-kappa B Kinase