Specific recognition of linear ubiquitin chains by NEMO is important for NF-kappaB activation.
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.
Rahighi
Simin
S
Structural Biology Research Center, Photon Factory, Institute of Materials Structure Science, High Energy Accelerator Research Organization (KEK), Tsukuba, Ibaraki, Japan.
Ikeda
Fumiyo
F
Kawasaki
Masato
M
Akutsu
Masato
M
Suzuki
Nobuhiro
N
Kato
Ryuichi
R
Kensche
Tobias
T
Uejima
Tamami
T
Bloor
Stuart
S
Komander
David
D
Randow
Felix
F
Wakatsuki
Soichi
S
Dikic
Ivan
I
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
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