Journal
EMBO JOURNAL
Volume 31, Issue 19, Pages 3833-3844Publisher
WILEY
DOI: 10.1038/emboj.2012.217
Keywords
E3 ligase; HHARI; Parkin; RNF31; TRIAD
Categories
Funding
- ERC
- EU
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Activation of the NF-kappa B pathway requires the formation of Met1-linked 'linear' ubiquitin chains on NEMO, which is catalysed by the Linear Ubiquitin Chain Assembly Complex (LUBAC) E3 consisting of HOIP, HOIL-1L and Sharpin. Here, we show that both LUBAC catalytic activity and LUBAC specificity for linear ubiquitin chain formation are embedded within the RING-IBR-RING (RBR) ubiquitin ligase subunit HOIP. Linear ubiquitin chain formation by HOIP proceeds via a two-step mechanism involving both RING and HECT E3-type activities. RING1-IBR catalyses the transfer of ubiquitin from the E2 onto RING2, to transiently form a HECT-like covalent thioester intermediate. Next, the ubiquitin is transferred from HOIP onto the N-terminus of a target ubiquitin. This transfer is facilitated by a unique region in the C-terminus of HOIP that we termed 'Linear ubiquitin chain Determining Domain' (LDD), which may coordinate the acceptor ubiquitin. Consistent with this mechanism, the RING2-LDD region was found to be important for NF-kappa B activation in cellular assays. These data show how HOIP combines a general RBR ubiquitin ligase mechanism with unique, LDD-dependent specificity for producing linear ubiquitin chains. The EMBO Journal (2012) 31, 3833-3844. doi:10.1038/emboj.2012.217; Published online 3 August 2012
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