UniProtKB/SwissProt variant VAR

NF-kappa-B essential modulator
Gene: IKBKG
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Variant information Variant position:

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

LP/P [Disclaimer] The variants are classified into three categories: LP/P, LB/B and US.

LP/P: likely pathogenic or pathogenic.
LB/B: likely benign or benign.
US: uncertain significance

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 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.

Variant rs137853331 [ dbSNP | Ensembl ]

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.

Type	Positions	Description
Chain	1 – 419	NF-kappa-B essential modulator
Region	242 – 350	Ubiquitin-binding (UBAN)
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 and interchain with MARCHF2)
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	302 – 302	K -> R. No effect on MARCH2F-mediated K48-linked ubiquitination.
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. No effect on MARCH2F-mediated K48-linked ubiquitination.
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	321 – 321	K -> R. No effect on MARCH2F-mediated K48-linked ubiquitination.
Mutagenesis	323 – 323	A -> D. Greatly impairs tandem ubiquitin binding.
Mutagenesis	325 – 325	K -> R. No effect on MARCH2F-mediated K48-linked ubiquitination.
Mutagenesis	326 – 326	K -> R. Abolishes MARCH2F-mediated K48-linked ubiquitination and subsequent suppression of antiviral and antibacterial innate immune response.
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. Abolished ubiquitin-binding.
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; GLU-315; ALA-323; 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; FUNCTION; 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;

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UniProtKB/Swiss-Prot variant pages

UniProtKB/Swiss-Prot Q9Y6K9: Variant p.Glu315Ala