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UniProtKB/Swiss-Prot Q9Y6K9: Variant p.Glu315Ala

NF-kappa-B essential modulator
Gene: IKBKG
Chromosomal location: Xq28
Variant information

Variant position:  315
The position of the amino-acid change on the UniProtKB canonical protein sequence.

Type of variant:  Disease [Disclaimer]
The variants are classified into three categories: Disease, Polymorphism and Unclassified.
  • Disease: Variants implicated in disease according to literature reports.
  • Polymorphism: Variants not reported to be implicated in disease.
  • Unclassified: Variants with uncertain implication in disease according to literature reports. Evidence against or in favor of a pathogenic role is limited and/or conflicting.

Residue change:  From Glutamate (E) to Alanine (A) at position 315 (E315A, p.Glu315Ala).
Indicates the amino acid change of the variant. The one-letter and three-letter codes for amino acids used in UniProtKB/Swiss-Prot are those adopted by the commission on Biochemical Nomenclature of the IUPAC-IUB.

Physico-chemical properties:  Change from medium size and acidic (E) to small size and hydrophobic (A)
The physico-chemical property of the reference and variant residues and the change implicated.

BLOSUM score:  -1
The score within a Blosum matrix for the corresponding wild-type to variant amino acid change. The log-odds score measures the logarithm for the ratio of the likelihood of two amino acids appearing by chance. The Blosum62 substitution matrix is used. This substitution matrix contains scores for all possible exchanges of one amino acid with another:
  • Lowest score: -4 (low probability of substitution).
  • Highest score: 11 (high probability of substitution).
More information can be found on the following page

Involvement in disease:  Immunodeficiency 33 (IMD33) [MIM:300636]: A X-linked recessive form of Mendelian susceptibility to mycobacterial disease, a rare condition characterized by predisposition to illness caused by moderately virulent mycobacterial species, such as Bacillus Calmette-Guerin (BCG) vaccine, environmental non-tuberculous mycobacteria, and by the more virulent Mycobacterium tuberculosis. Other microorganisms rarely cause severe clinical disease in individuals with susceptibility to mycobacterial infections, with the exception of Salmonella which infects less than 50% of these individuals. {ECO:0000269|PubMed:16818673, ECO:0000269|PubMed:19185524, ECO:0000269|PubMed:19854204}. Note=Disease susceptibility is associated with variations affecting the gene represented in this entry.
The name and a short description of the disease associated with the variant. For more information about the disease, the user can refer to OMIM, following the link provided after the disease acronym.

Variant description:  In IMD33; greatly impairs tandem ubiquitin binding. Impairs oligomerization, impairs binding of 'Lys-63'-linked ubiuitin and linear tetra-ubiquitin, impairs TNF-induced NF-kappa-B activation.
Any additional useful information about the variant.

Other resources:  
Links to websites of interest for the variant.



Sequence information

Variant position:  315
The position of the amino-acid change on the UniProtKB canonical protein sequence.

Protein sequence length:  419
The length of the canonical sequence.

Location on the sequence:   METVPVLKAQADIYKADFQA  E RQAREKLAEKKELLQEQLEQ
The residue change on the sequence. Unless the variant is located at the beginning or at the end of the protein sequence, both residues upstream (20) and downstream (20) of the variant will be shown.

Residue conservation: 
The multiple alignment of the region surrounding the variant against various orthologous sequences.

Human                         METVPVLKAQADIYKADFQAERQAREKLAEKKELLQEQLEQ

Mouse                         METVPVLKAQADIYKADFQAERHAREKLVEKKEYLQEQLEQ

Rat                           METVPVLKAQADIYKADFQAERHAREKLVERKELLQEQLEQ

Pig                           METVPVLKAQADIYKADFQAERQAREQLAERKELLQEQLEQ

Bovine                        METVPVLKAQADIYKADFQAERQAREKLAEKKEFLQEQLEQ

Drosophila                    -EVIKGLQIQNDIYRRDFEMERADREKNAGEKDQYLMDLRS

Sequence annotation in neighborhood:  
The regions or sites of interest surrounding the variant. In general the features listed are posttranslational modifications, binding sites, enzyme active sites, local secondary structure or other characteristics reported in the cited references. The "Sequence annotation in neighborhood" lines have a fixed format:
  • Type: the type of sequence feature.
  • Positions: endpoints of the sequence feature.
  • Description: contains additional information about the feature.

TypePositionsDescription
Chain 1 – 419 NF-kappa-B essential modulator
Region 242 – 350 Ubiquitin-binding (UBD)
Region 246 – 365 Self-association
Region 251 – 419 Required for interaction with TNFAIP3
Coiled coil 49 – 356
Cross 302 – 302 Glycyl lysine isopeptide (Lys-Gly) (interchain with G-Cter in ubiquitin)
Cross 309 – 309 Glycyl lysine isopeptide (Lys-Gly) (interchain with G-Cter in SUMO); alternate
Cross 309 – 309 Glycyl lysine isopeptide (Lys-Gly) (interchain with G-Cter in ubiquitin); alternate
Cross 321 – 321 Glycyl lysine isopeptide (Lys-Gly) (interchain with G-Cter in ubiquitin)
Cross 325 – 325 Glycyl lysine isopeptide (Lys-Gly) (interchain with G-Cter in ubiquitin)
Cross 326 – 326 Glycyl lysine isopeptide (Lys-Gly) (interchain with G-Cter in ubiquitin)
Mutagenesis 296 – 296 E -> A. No effet on oligomerization,impairs binding of 'Lys-63'-linked ubiuitin and linear tetra-ubiquitin, impairs TNF-induced NF-kappa-B activation.
Mutagenesis 300 – 300 V -> D. Greatly impairs tandem ubiquitin binding.
Mutagenesis 301 – 301 L -> A. Impairs tandem ubiquitin binding.
Mutagenesis 304 – 304 Q -> A. Complete loss of cleavage by HAV protease 3c.
Mutagenesis 304 – 304 Q -> A. Impairs tandem ubiquitin binding.
Mutagenesis 307 – 307 I -> N. Greatly impairs tandem ubiquitin binding.
Mutagenesis 308 – 308 Y -> A. Greatly impairs tandem ubiquitin binding.
Mutagenesis 309 – 309 K -> A. Partial abolition of sumoylation. Abolishes sumoylation and IKK activation; when associated with A-277.
Mutagenesis 312 – 312 F -> A. Greatly impairs tandem ubiquitin binding,impairs oligomerization, impairs TNF-induced NF-kappa-B activation.
Mutagenesis 312 – 312 F -> W. MNo effet on oligomerization, preferentially binds tri-ubiquitin chains ('Lys-48' or 'Lys-63'-linked).
Mutagenesis 312 – 312 F -> Y. Impairs tandem ubiquitin binding.
Mutagenesis 313 – 313 Q -> A. Impairs tandem ubiquitin binding.
Mutagenesis 315 – 315 E -> Q. Greatly impairs tandem ubiquitin binding.
Mutagenesis 317 – 317 Q -> AW. Greatly impairs tandem ubiquitin binding.
Mutagenesis 323 – 323 A -> D. Greatly impairs tandem ubiquitin binding.
Mutagenesis 329 – 329 L -> A. Impairs oligomerization, impairs binding of 'Lys-63'-linked ubiuitin, impairs TNF-induced NF-kappa-B activation; when associated with A-336.
Mutagenesis 329 – 329 L -> P. Abolishes binding to polyubiquitin.
Helix 297 – 341


Literature citations

DARPin-assisted crystallography of the CC2-LZ domain of NEMO reveals a coupling between dimerization and ubiquitin binding.
Grubisha O.; Kaminska M.; Duquerroy S.; Fontan E.; Cordier F.; Haouz A.; Raynal B.; Chiaravalli J.; Delepierre M.; Israel A.; Veron M.; Agou F.;
J. Mol. Biol. 395:89-104(2010)
Cited for: MUTAGENESIS OF GLU-296; PHE-312; LEU-329 AND LEU-336; CHARACTERIZATION OF VARIANTS IMD33 ALA-315 AND PRO-323;

Structural basis for recognition of diubiquitins by NEMO.
Lo Y.C.; Lin S.C.; Rospigliosi C.C.; Conze D.B.; Wu C.J.; Ashwell J.D.; Eliezer D.; Wu H.;
Mol. Cell 33:602-615(2009)
Cited for: X-RAY CRYSTALLOGRAPHY (3.2 ANGSTROMS) OF 246-337; UBIQUITIN-BINDING; MUTAGENESIS OF VAL-300; LEU-301; GLN-304; ILE-307; TYR-308; PHE-312; GLN-313 AND GLN-317; CHARACTERIZATION OF VARIANT EDAID1 ASN-311; CHARACTERIZATION OF VARIANT IMD33 ALA-315; CHARACTERIZATION OF VARIANTS GLN-319 AND IP PRO-323;

X-linked susceptibility to mycobacteria is caused by mutations in NEMO impairing CD40-dependent IL-12 production.
Filipe-Santos O.; Bustamante J.; Haverkamp M.H.; Vinolo E.; Ku C.-L.; Puel A.; Frucht D.M.; Christel K.; von Bernuth H.; Jouanguy E.; Feinberg J.; Durandy A.; Senechal B.; Chapgier A.; Vogt G.; de Beaucoudrey L.; Fieschi C.; Picard C.; Garfa M.; Chemli J.; Bejaoui M.; Tsolia M.N.; Kutukculer N.; Plebani A.; Notarangelo L.; Bodemer C.; Geissmann F.; Israeel A.; Veron M.; Knackstedt M.; Barbouche R.; Abel L.; Magdorf K.; Gendrel D.; Agou F.; Holland S.M.; Casanova J.-L.;
J. Exp. Med. 203:1745-1759(2006)
Cited for: VARIANTS IMD33 ALA-315 AND GLN-319;

Disclaimer: Any medical or genetic information present in this entry is provided for research, educational and informational purposes only. They are not in any way intended to be used as a substitute for professional medical advice, diagnostic, treatment or care.