View source for 2jvy


==Solution Structure of the EDA-ID-related C417F mutant of human NEMO zinc finger==
<StructureSection load='2jvy' size='340' side='right'caption='[[2jvy]]' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[2jvy]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full experimental information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2JVY OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=2JVY FirstGlance]. <br>
</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">Solution NMR</td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=ZN:ZINC+ION'>ZN</scene></td></tr>
<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=2jvy FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2jvy OCA], [https://pdbe.org/2jvy PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=2jvy RCSB], [https://www.ebi.ac.uk/pdbsum/2jvy PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=2jvy ProSAT]</span></td></tr>
</table>
== Disease ==
[https://www.uniprot.org/uniprot/NEMO_HUMAN NEMO_HUMAN] Defects in IKBKG are the cause of ectodermal dysplasia anhidrotic with immunodeficiency X-linked (EDAID) [MIM:[https://omim.org/entry/300291 300291]; also known as hypohidrotic ectodermal dysplasia with immunodeficiency (HED-ID). Is a form of ectoderma dysplasia, a heterogeneous group of disorders due to abnormal development of two or more ectodermal structures. Characterized by absence of sweat glands, sparse scalp hair, rare conical teeth and immunological abnormalities resulting in severe infectious diseases.<ref>PMID:14651848</ref> <ref>PMID:16547522</ref> <ref>PMID:21606507</ref> <ref>PMID:19185524</ref> <ref>PMID:11047757</ref> <ref>PMID:11242109</ref> <ref>PMID:11224521</ref> <ref>PMID:12045264</ref> <ref>PMID:15100680</ref>   Defects in IKBKG are the cause of ectodermal dysplasia anhidrotic with immunodeficiency-osteopetrosis-lymphedema (OLEDAID) [MIM:[https://omim.org/entry/300301 300301].  Defects in IKBKG are a cause of immunodeficiency NEMO-related without anhidrotic ectodermal dysplasia (NEMOID) [MIM:[https://omim.org/entry/300584 300584]; also called immunodeficiency without anhidrotic ectodermal dysplasia, isolated immunodeficiency or pure immunodeficiency. Patients manifest immunodeficiency not associated with other abnormalities, and resulting in increased infection susceptibility. Patients suffer from multiple episodes of infectious diseases.<ref>PMID:15100680</ref> <ref>PMID:15356572</ref>   Defects in IKBKG are the cause of susceptibility to X-linked familial atypical micobacteriosis type 1 (AMCBX1) [MIM:[https://omim.org/entry/300636 300636]; also known as X-linked disseminated atypical mycobacterial infection type 1 or X-linked susceptibility to mycobacterial disease type 1. AMCBX1 is the X-linked recessive form of Mendelian susceptibility to mycobacterial disease (MSMD). MSMD is a congenital syndrome resulting in predisposition to clinical disease caused by weakly virulent mycobacterial species, such as bacillus Calmette-Guerin vaccines and non-tuberculous, environmental mycobacteria. Patients are also susceptible to the more virulent species Mycobacterium tuberculosis.<ref>PMID:19185524</ref> <ref>PMID:16818673</ref>   Defects in IKBKG are the cause of recurrent isolated invasive pneumococcal disease type 2 (IPD2) [MIM:[https://omim.org/entry/300640 300640]. Recurrent invasive pneumococcal disease (IPD) is defined as two episodes of IPD occurring at least 1 month apart, whether caused by the same or different serotypes or strains. Recurrent IPD occurs in at least 2% of patients in most series, making IPD the most important known risk factor for subsequent IPD.<ref>PMID:16950813</ref>   Defects in IKBKG are the cause of incontinentia pigmenti (IP) [MIM:[https://omim.org/entry/308300 308300]; formerly designed familial incontinentia pigmenti type II (IP2). IP is a genodermatosis usually prenatally lethal in males. In affected females, it causes abnormalities of the skin, hair, eyes, nails, teeth, skeleton, heart, and central nervous system. The prominent skin signs occur in four classic cutaneous stages: perinatal inflammatory vesicles, verrucous patches, a distinctive pattern of hyperpigmentation and dermal scarring.<ref>PMID:20010814</ref> <ref>PMID:17728323</ref> <ref>PMID:19185524</ref> <ref>PMID:16950813</ref> <ref>PMID:10839543</ref> <ref>PMID:19033441</ref> <ref>PMID:11590134</ref> <ref>PMID:15229184</ref> 
== Function ==
[https://www.uniprot.org/uniprot/NEMO_HUMAN NEMO_HUMAN] Regulatory subunit of the IKK core complex which phosphorylates inhibitors of NF-kappa-B thus leading to the dissociation of the inhibitor/NF-kappa-B complex and ultimately the degradation of the inhibitor. Its binding to scaffolding polyubiquitin seems to play a role in IKK activation by multiple signaling receptor pathways. However, the specific type of polyubiquitin recognized upon cell stimulation (either 'Lys-63'-linked or linear polyubiquitin) and its functional importance is reported conflictingly. Also considered to be a mediator for TAX activation of NF-kappa-B. Could be implicated in NF-kappa-B-mediated protection from cytokine toxicity (By similarity). Essential for viral activation of IRF3. Involved in TLR3- and IFIH1-mediated antiviral innate response; this function requires 'Lys-27'-linked polyubiquitination.<ref>PMID:14695475</ref> <ref>PMID:19854139</ref> <ref>PMID:20724660</ref> 
<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
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.

Solution Structure of NEMO Zinc Finger and Impact of an Anhidrotic Ectodermal Dysplasia with Immunodeficiency-related Point Mutation.,Cordier F, Vinolo E, Veron M, Delepierre M, Agou F J Mol Biol. 2008 Jan 30;. PMID:18313693<ref>PMID:18313693</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 2jvy" style="background-color:#fffaf0;"></div>
== References ==
<references/>
__TOC__
</StructureSection>
[[Category: Homo sapiens]]
[[Category: Large Structures]]
[[Category: Agou F]]
[[Category: Cordier F]]
[[Category: Delepierre M]]
[[Category: Veron M]]
[[Category: Vinolo E]]