The NF-kappaB (nuclear factor kappaB) regulator A20 antagonises IKK [IkappaB
(inhibitor of kappaB) kinase] activation by modulating Lys63-linked
polyubiquitination of cytokine-receptor-associated factors including TRAF2/6
(tumour-necrosis-factor-receptor-associated factor 2/6) and RIP1
(receptor-interacting protein 1). In the present paper we describe the crystal
structure of the N-terminal OTU (ovarian tumour) deubiquitinase domain of A20,
which differs from other deubiquitinases but shares the minimal catalytic core
with otubain-2. Analysis of conserved surface regions allows prediction of
ubiquitin-binding sites for the proximal and distal ubiquitin molecules.
Structural and biochemical analysis suggests a novel architecture of the
catalytic triad, which might be present in a subset of OTU domains including
Cezanne and TRABID (TRAF-binding domain). Biochemical analysis shows a
preference of the isolated A20 OTU domain for Lys48-linked tetraubiquitin in
vitro suggesting that additional specificity factors might be required for the
physiological function of A20 in cells.
