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 have been found in patients and disease-association is reported in literature. However, this classification is not a definitive assessment of variant pathogenicity.
  • Polymorphism: No disease-association has been reported.
  • Unclassified: Variants have been found in patients but disease-association remains unclear.

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

Variant description:  In AMCBX1; greatly impairs tandem ubiquitin binding.
Any additional useful information about 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

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. 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 -> A. Impairs oligomerization, impairs binding of 'Lys-63'-linked ubiuitin and linear tetra-ubiquitin, impairs TNF-induced NF-kappa-B activation.
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 323 – 323 A -> P. Impairs oligomerization, greatly impairs binding of 'Lys-63'-linked ubiuitin, and linear tetra-ubiquitin, impairs TNF-induced NF-kappa-B activation.
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 280 – 321


Literature citations

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 EDAID ASN-311; CHARACTERIZATION OF VARIANT AMCBX1 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 AMCBX1 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.