TY - JOUR
T1 - Structural Basis for Recognition of Diubiquitins by NEMO
AU - Lo, Yu Chih
AU - Lin, Su Chang
AU - Rospigliosi, Carla C.
AU - Conze, Dietrich B.
AU - Wu, Chuan Jin
AU - Ashwell, Jonathan D.
AU - Eliezer, David
AU - Wu, Hao
PY - 2009/3/13
Y1 - 2009/3/13
N2 - 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.
AB - 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.
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U2 - 10.1016/j.molcel.2009.01.012
DO - 10.1016/j.molcel.2009.01.012
M3 - Article
C2 - 19185524
AN - SCOPUS:61649103747
SN - 1097-2765
VL - 33
SP - 602
EP - 615
JO - Molecular Cell
JF - Molecular Cell
IS - 5
ER -