PDBsum entry 2zvn

Signaling protein/transcription

PDB id: 2zvn

Contents

Protein chains

148 a.a. *

85 a.a. *

Waters ×65

* Residue conservation analysis

PDB id:

2zvn

Name:

Signaling protein/transcription

Title:

Nemo cozi domain incomplex with diubiquitin in p212121 space group

Structure:

Ubc protein. Chain: a, g, c, e. Fragment: ubiquitin. Engineered: yes. Nf-kappa-b essential modulator. Chain: b, d, f, h. Fragment: cc2-lz, cozi domain. Synonym: nemo, nf-kappa-b essential modifier, inhibitor of nuclear factor kappa-b kinase subunit gamma, ikb kinase subunit gamma, i-

Source:

Homo sapiens. Human. Organism_taxid: 9606. Expressed in: escherichia coli. Expression_system_taxid: 562. Mus musculus. Mouse. Organism_taxid: 10090.

Resolution:

3.00Å R-factor: 0.263 R-free: 0.303

Authors:

S.Rahighi,F.Ikeda,M.Kawasaki,M.Akutsu,N.Suzuki,R.Kato,T.Kensche, T.Uejima,S.Bloor,D.Komander,F.Randow,S.Wakatsuki,I.Dikic

Key ref:

S.Rahighi et al. (2009). Specific recognition of linear ubiquitin chains by NEMO is important for NF-kappaB activation. Cell, 136, 1098-1109. PubMed id: 19303852 DOI: 10.1016/j.cell.2009.03.007

Date:

12-Nov-08 Release date: 24-Mar-09

Protein chains

P0CG48  (UBC_HUMAN) -  Polyubiquitin-C from Homo sapiens

Seq: 685 a.a.

Struc: 148 a.a.

Protein chains

O88522  (NEMO_MOUSE) -  NF-kappa-B essential modulator from Mus musculus

Seq: 412 a.a.

Struc: 85 a.a.*

* PDB and UniProt seqs differ at 1 residue position (black cross)

Enzyme reactions

• Enzyme class: Chains A, G, B, D, C, E, F, H: E.C.?

DOI no: 10.1016/j.cell.2009.03.007

Cell 136:1098-1109 (2009)

PubMed id: 19303852

Specific recognition of linear ubiquitin chains by NEMO is important for NF-kappaB activation.

S.Rahighi, F.Ikeda, M.Kawasaki, M.Akutsu, N.Suzuki, R.Kato, T.Kensche, T.Uejima, S.Bloor, D.Komander, F.Randow, S.Wakatsuki, I.Dikic.

ABSTRACT

Activation of nuclear factor-kappaB (NF-kappaB), a key mediator of inducible transcription in immunity, requires binding of NF-kappaB essential modulator (NEMO) to ubiquitinated substrates. Here, we report that the UBAN (ubiquitin binding in ABIN and NEMO) motif of NEMO selectively binds linear (head-to-tail) ubiquitin chains. Crystal structures of the UBAN motif revealed a parallel coiled-coil dimer that formed a heterotetrameric complex with two linear diubiquitin molecules. The UBAN dimer contacted all four ubiquitin moieties, and the integrity of each binding site was required for efficient NF-kappaB activation. Binding occurred via a surface on the proximal ubiquitin moiety and the canonical Ile44 surface on the distal one, thereby providing specificity for linear chain recognition. Residues of NEMO involved in binding linear ubiquitin chains are required for NF-kappaB activation by TNF-alpha and other agonists, providing an explanation for the detrimental effect of NEMO mutations in patients suffering from X-linked ectodermal dysplasia and immunodeficiency.

Selected figure(s)

Figure 3.
Figure 3. Structure of NEMO[CoZi] in Complex with Diubiquitin
(A and B) Overall structure of the NEMO[CoZi]●diubiquitin complex in two orthogonal views. The two chains of NEMO are colored in green and violet; Ub[distal] is shown in orange, and Ub[proximal] in gold.
(C and D) Open-book representation of NEMO UBAN motif recognition of distal and proximal ubiquitin moities. In (C), residues from Ub[distal] (orange) and Ub[proximal] (gold) that interact with the NEMO UBAN motif are labeled on the diubiquitin surface, indicating two mutually exclusive binding surfaces. (D) shows a surface representation of NEMO UBAN motif colored according to the interaction partner, Ub[distal] (orange) and Ub[proximal] (gold) and both (yellow). Residues involved in the interaction are labeled.
(E and F) Open-book representations of the NEMO[CoZi]●diubiquitin complex. The surfaces of linear diubiquitin (E) and NEMO[CoZi] (F) are colored according to their electrostatic surface potential (blue, positive; red, negative). In (F), the bound diubiquitin is drawn as a transparent ribbon model; Ub[distal] in orange and Ub[proximal] in gold.
(G and I) Stereo views of the interactions of the Ub[distal] (G) and Ub[proximal] (I) with the NEMO UBAN motif colored as in (A). Interacting residues are shown as sticks. Hydrogen bonds and salt bridges are indicated as blue dashed lines.
(H and J) Schematic diagrams of the interactions of Ub[distal] (H) and Ub[proximal] (J) with the NEMO UBAN motif. The two chains of NEMO are shown in green and violet, and Ub[distal] and Ub[proximal] in orange and gold, respectively. Dashed orange and yellow lines indicate hydrogen bonds and salt bridges, respectively. Hydrophobic interactions are shown as dashed red lines. Residues in the NEMO UBAN domain whose mutations are found in ectodermal dysplasia (D304, E308, and R312) are circled in red.

Figure 7.
Figure 7. A Model of Ectodermal Dysplasia Mutations in NEMO
Mutations in NEMO UBAN domain found in ectodermal dysplasia (D304, E308, and R312) (red) are all involved in binding to linear diubiquitin at amino acids R72, L73, and R74 in distal ubiquitin molecule (orange) or Q2, F4, and E64 in proximal ubiquitin molecule (gold).

The above figures are reprinted by permission from Cell Press: Cell (2009, 136, 1098-1109) copyright 2009.

Figures were selected by an automated process.