The E3 ligase HOIP specifies linear ubiquitin chain assembly through its RING-IBR-RING domain and the unique LDD extension

Activation of the NF‐κB 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‐κB 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.

• Publication year

  2012

• Venue

  EMBO Journal

• Publication date

  2012-08-03

• Fields of study

  Biology, Medicine, Chemistry

• Identifiers
  DOI 10.1038/emboj.2012.217PMID 22863777PMCID 3463842
• External record

  Open on Semantic Scholar

• Source metadata

  Semantic Scholar, PubMed

• No claims are published for this paper.

• No concepts are published for this paper.

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