PDBsum entry 2jvy

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protein metals links
Metal binding protein PDB id
Protein chain
28 a.a.
PDB id:
Name: Metal binding protein
Title: Solution structure of the eda-id-related c417f mutant of human nemo zinc finger
Structure: Nf-kappa-b essential modulator. Chain: a. Fragment: zinc finger domain. Synonym: nemo, nf-kappa-b essential modifier, inhibitor of nuclear factor kappa-b kinase subunit gamma, ikb kinase subunit gamma, i-kappa-b kinase gamma, ikk-gamma, ikkg, ikb kinase-associated protein 1, ikkap1, fip-3. Engineered: yes. Mutation: yes.
Source: Synthetic: yes. Other_details: synthetic peptide, termini-blocked by n- acetyl and c-amide groups
NMR struc: 10 models
Authors: F.Cordier,E.Vinolo,M.Veron,M.Delepierre,F.Agou
Key ref:
F.Cordier et al. (2008). Solution structure of NEMO zinc finger and impact of an anhidrotic ectodermal dysplasia with immunodeficiency-related point mutation. J Mol Biol, 377, 1419-1432. PubMed id: 18313693 DOI: 10.1016/j.jmb.2008.01.048
28-Sep-07     Release date:   18-Mar-08    
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Protein chain
Pfam   ArchSchema ?
Q9Y6K9  (NEMO_HUMAN) -  NF-kappa-B essential modulator
419 a.a.
28 a.a.*
Key:    PfamA domain  PfamB domain  Secondary structure
* PDB and UniProt seqs differ at 3 residue positions (black crosses)


DOI no: 10.1016/j.jmb.2008.01.048 J Mol Biol 377:1419-1432 (2008)
PubMed id: 18313693  
Solution structure of NEMO zinc finger and impact of an anhidrotic ectodermal dysplasia with immunodeficiency-related point mutation.
F.Cordier, E.Vinolo, M.Véron, M.Delepierre, F.Agou.
The regulatory NEMO (NF-kappaB essential modulator) protein has a crucial role in the canonical NF-kappaB signaling pathway notably involved in immune and inflammatory responses, apoptosis and oncogenesis. The regulatory domain is located in the C-terminal half of NEMO and contains a classical CCHC-type zinc finger (ZF). We have investigated the structural and functional effects of a cysteine to phenylalanine point mutation (C417F) in the ZF motif, identified in patients with anhidrotic ectodermal dysplasia with immunodeficiency. The solution structures of the wild type and mutant ZF were determined by NMR. Remarkably, the mutant adopts a global betabetaalpha fold similar to that of the wild type and retains thermodynamic stability, i.e., the ability to bind zinc with a native-like affinity, although the last zinc-chelating residue is missing. However, the mutation induces enhanced dynamics in the motif and leads to an important loss of stability. A detailed analysis of the wild type solution structure and experimental evidences led to the identification of two possible protein-binding surfaces that are largely destabilized in the mutant. This is sufficient to alter NEMO function, since functional complementation assays using NEMO-deficient pre-B and T lymphocytes show that full-length C417F pathogenic NEMO leads to a partial to strong defect in LPS, IL-1beta and TNF-alpha-induced NF-kappaB activation, respectively, as compared to wild type NEMO. Altogether, these results shed light onto the role of NEMO ZF as a protein-binding motif and show that a precise structural integrity of the ZF should be preserved to lead to a functional protein-recognition motif triggering full NF-kappaB activation.
  Selected figure(s)  
Figure 4.
Fig. 4. Solution structure of NEMO wild type zinc finger and comparison to classical fingers. (a and b) Ribbon representation of a representative structure on top of the NMR ensemble. The zinc atom and ligating side chains (C6, C9, H22, C26) are shown in yellow, conserved residues (F4, L19) in green, the aromatic swap (Y11, A13) in magenta and V23, M24 and E25 in orange. The tyrosine Y11 hydroxyl group is shown in red and lysine K8 in blue, with its ε-amino group in cyan. (c) Superposition of ZFY-6 (CCHH[27], PDB code 5znf,^37 blue), FOG-F3 (CCHH[26], 1srk,^43 green) and USH-F9 (CCHC[27], 1fu9,^30 gray) onto NEMO ZF (CCHC[26], red). Backbone pairwise RMSD (sequence identity) to NEMO ZF for residues 4–26 are 0.66 Å (23.1%), 1.00 Å (16.7%) and 1.41 Å (16.7%), respectively. Side chains are depicted for the zinc-chelating residues (balls and sticks), for the “conserved” residues at position 4, 19 (thick sticks) and for the aromatic residue (thin sticks) at position 11 (“swap”) or 13 (“consensus”).
Figure 5.
Fig. 5. Solution structure of the C417F mutant zinc finger. (a and b) Ribbon representation of a representative structure of ZF-C417F on top of the NMR ensemble. The color-coding is the same as that used in Fig. 4a. Side chains of the highly flexible C-terminal residues (V23, M24, E25) and of the F26 mutated residue are shown in orange and yellow, respectively. The backbone carbonyl group of H22 is represented as red ball and stick. A water molecule probably stabilizing the zinc-coordination site (see the text) is shown as red/white balls and sticks.
  The above figures are reprinted by permission from Elsevier: J Mol Biol (2008, 377, 1419-1432) copyright 2008.  
  Figures were selected by an automated process.  

Literature references that cite this PDB file's key reference

  PubMed id Reference
21135870 C.Zheng, Q.Yin, and H.Wu (2011).
Structural studies of NF-κB signaling.
  Cell Res, 21, 183-195.  
21423167 G.Xu, Y.C.Lo, Q.Li, G.Napolitano, X.Wu, X.Jiang, M.Dreano, M.Karin, and H.Wu (2011).
Crystal structure of inhibitor of κB kinase β.
  Nature, 472, 325-330.
PDB codes: 3qa8 3qad 3rzf
20345847 A.S.Shifera (2010).
The zinc finger domain of IKKγ (NEMO) protein in health and disease.
  J Cell Mol Med, 14, 2404-2414.  
19763089 E.Laplantine, E.Fontan, J.Chiaravalli, T.Lopez, G.Lakisic, M.Véron, F.Agou, and A.Israël (2009).
NEMO specifically recognizes K63-linked poly-ubiquitin chains through a new bipartite ubiquitin-binding domain.
  EMBO J, 28, 2885-2895.  
19033441 F.Cordier, O.Grubisha, F.Traincard, M.Véron, M.Delepierre, and F.Agou (2009).
The Zinc Finger of NEMO Is a Functional Ubiquitin-binding Domain.
  J Biol Chem, 284, 2902-2907.  
19422324 F.J.Ivins, M.G.Montgomery, S.J.Smith, A.C.Morris-Davies, I.A.Taylor, and K.Rittinger (2009).
NEMO oligomerization and its ubiquitin-binding properties.
  Biochem J, 421, 243-251.  
19303852 S.Rahighi, F.Ikeda, M.Kawasaki, M.Akutsu, N.Suzuki, R.Kato, T.Kensche, T.Uejima, S.Bloor, D.Komander, F.Randow, S.Wakatsuki, and I.Dikic (2009).
Specific recognition of linear ubiquitin chains by NEMO is important for NF-kappaB activation.
  Cell, 136, 1098-1109.
PDB codes: 2zvn 2zvo 3f89
  20066103 T.Huxford, and G.Ghosh (2009).
A structural guide to proteins of the NF-kappaB signaling module.
  Cold Spring Harbor Perspect Biol, 1, a000075.  
18851874 E.P.Hanson, L.Monaco-Shawver, L.A.Solt, L.A.Madge, P.P.Banerjee, M.J.May, and J.S.Orange (2008).
Hypomorphic nuclear factor-kappaB essential modulator mutation database and reconstitution system identifies phenotypic and immunologic diversity.
  J Allergy Clin Immunol, 122, 1169.  
The most recent references are shown first. Citation data come partly from CiteXplore and partly from an automated harvesting procedure. Note that this is likely to be only a partial list as not all journals are covered by either method. However, we are continually building up the citation data so more and more references will be included with time. Where a reference describes a PDB structure, the PDB codes are shown on the right.