Structural Basis for Recognition of Diubiquitins by NEMO

Yu Chih Lo, Su Chang Lin, Carla C. Rospigliosi, Dietrich B. Conze, Chuan Jin Wu, Jonathan D. Ashwell, David Eliezer, Hao Wu

Research output: Contribution to journalArticlepeer-review

187 Citations (Scopus)

Abstract

NEMO is the regulatory subunit of the IκB kinase (IKK) in NF-κB activation, and its CC2-LZ region interacts with Lys63 (K63)-linked polyubiquitin to recruit IKK to receptor signaling complexes. In vitro, CC2-LZ also interacts with tandem diubiquitin. Here we report the crystal structure of CC2-LZ with two dimeric coiled coils representing CC2 and LZ, respectively. Surprisingly, mutagenesis and nuclear magnetic resonance experiments reveal that the binding sites for diubiquitins at LZ are composites of both chains and that each ubiquitin in diubiquitins interacts with symmetrical NEMO asymmetrically. For tandem diubiquitin, the first ubiquitin uses the conserved hydrophobic patch and the C-terminal tail, while the second ubiquitin uses an adjacent surface patch. For K63-linked diubiquitin, the proximal ubiquitin uses its conserved hydrophobic patch, while the distal ubiquitin mostly employs the C-terminal arm including the K63 linkage residue. These studies uncover the energetics and geometry for mutual recognition of NEMO and diubiquitins.

Original languageEnglish
Pages (from-to)602-615
Number of pages14
JournalMolecular Cell
Volume33
Issue number5
DOIs
Publication statusPublished - 2009 Mar 13

All Science Journal Classification (ASJC) codes

  • Molecular Biology
  • Cell Biology

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