Specific recognition of linear ubiquitin chains by NEMO is important for NF-kappaB activation - PubMed (original) (raw)

. 2009 Mar 20;136(6):1098-109.

doi: 10.1016/j.cell.2009.03.007.

Fumiyo Ikeda, Masato Kawasaki, Masato Akutsu, Nobuhiro Suzuki, Ryuichi Kato, Tobias Kensche, Tamami Uejima, Stuart Bloor, David Komander, Felix Randow, Soichi Wakatsuki, Ivan Dikic

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Specific recognition of linear ubiquitin chains by NEMO is important for NF-kappaB activation

Simin Rahighi et al. Cell. 2009.

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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.

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