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UniProtKB/Swiss-Prot O43918: Variant p.Cys311Tyr

Autoimmune regulator
Gene: AIRE
Variant information

Variant position:  311
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 Cysteine (C) to Tyrosine (Y) at position 311 (C311Y, p.Cys311Tyr).
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 polar (C) to large size and aromatic (Y)
The physico-chemical property of the reference and variant residues and the change implicated.

BLOSUM score:  -2
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 APS1; impairs zinc binding and folding of the PHD-type 1 zinc finger; dominant-negative effect on the regulation of target gene transcription; no effect on doted nuclear localization; dominant-negative effect on regulation of target gene transcription.
Any additional useful information about the variant.

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



Sequence information

Variant position:  311
The position of the amino-acid change on the UniProtKB canonical protein sequence.

Protein sequence length:  545
The length of the canonical sequence.

Location on the sequence:   LHQKNEDECAVCRDGGELIC  C DGCPRAFHLACLSPPLREIP
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                         LHQKNEDECAVCRDGGELICCDGCPRAFHLACLSPPLREIP

Mouse                         VNQKNEDECAVCHDGGELICCDGCPRAFHLACLSPPLQEIP

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 – 545 Autoimmune regulator
Zinc finger 296 – 343 PHD-type 1
Region 304 – 312 Interaction with histone H3 not methylated at 'Lys-4'
Alternative sequence 293 – 293 Q -> PVCMGVSCLCQ. In isoform 4.
Mutagenesis 295 – 295 N -> A. Abolishes interaction with histone H3.
Mutagenesis 297 – 297 D -> A. Strongly reduces interaction with unmethylated histone H3 and abolishes interaction with histone H3 trimethylated at 'Lys-4'. No effect on doted nuclear localization. Dominant-negative effect on target gene transcription.
Mutagenesis 298 – 298 E -> A. Reduces interaction with histone H3.
Mutagenesis 302 – 302 C -> P. Reduces transcriptional activation.
Mutagenesis 303 – 303 R -> P. Alters protein folding and abolishes interaction with histone H3. No effect on doted nuclear localization. Dominant-negative effect on target gene transcription.
Mutagenesis 304 – 304 D -> A. Strongly reduces interaction with histone H3.
Mutagenesis 307 – 307 E -> A. Reduces interaction with histone H3.
Mutagenesis 312 – 312 D -> A. Abolishes interaction with histone H3.
Mutagenesis 312 – 312 D -> N. No effect on doted nuclear localization. Dominant-negative effect on target gene transcription.


Literature citations

Mutations in the AIRE gene: effects on subcellular location and transactivation function of the autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy protein.
Bjeorses P.; Halonen M.; Palvimo J.J.; Kolmer M.; Aaltonen J.; Ellonen P.; Perheentupa J.; Ulmanen I.; Peltonen L.;
Am. J. Hum. Genet. 66:378-392(2000)
Cited for: SUBCELLULAR LOCATION; VARIANTS APS1 LEU-80; CYS-85; TYR-311 AND GLN-326;

The autoimmune regulator PHD finger binds to non-methylated histone H3K4 to activate gene expression.
Org T.; Chignola F.; Hetenyi C.; Gaetani M.; Rebane A.; Liiv I.; Maran U.; Mollica L.; Bottomley M.J.; Musco G.; Peterson P.;
EMBO Rep. 9:370-376(2008)
Cited for: INTERACTION WITH HISTONE H3 NON-METHYLATED OR MONO-METHYLATED AT LYS-4; FUNCTION; MUTAGENESIS OF ASP-297 AND ASP-312; CHARACTERIZATION OF VARIANTS APS1 MET-301 AND TYR-311;

NMR structure of the first PHD finger of autoimmune regulator protein (AIRE1). Insights into autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED) disease.
Bottomley M.J.; Stier G.; Pennacchini D.; Legube G.; Simon B.; Akhtar A.; Sattler M.; Musco G.;
J. Biol. Chem. 280:11505-11512(2005)
Cited for: STRUCTURE BY NMR OF 293-354 IN COMPLEX WITH ZINC IONS; CHARACTERIZATION OF VARIANTS APS1 MET-301; TYR-311 AND GLN-326;

Structure and site-specific recognition of histone H3 by the PHD finger of human autoimmune regulator.
Chakravarty S.; Zeng L.; Zhou M.-M.;
Structure 17:670-679(2009)
Cited for: STRUCTURE BY NMR OF 294-347 IN COMPLEX WITH ZINC IONS AND UNMETHYLATED HISTONE H3 N-TERMINUS; CHARACTERIZATION OF VARIANTS APS1 MET-301; TYR-311; LEU-326 AND GLN-326;

APECED mutations in the autoimmune regulator (AIRE) gene.
Heino M.; Peterson P.; Kudoh J.; Shimizu N.; Antonarakis S.E.; Scott H.S.; Krohn K.J.E.;
Hum. Mutat. 18:205-211(2001)
Cited for: VARIANTS APS1 LEU-15; MET-16; PRO-28; PR0-29; ARG-78; LEU-80; GLU-83; CYS-85; CYS-90; ARG-93; MET-301; TYR-311 AND GLN-326; VARIANT ARG-278;

AIRE mutations and human leukocyte antigen genotypes as determinants of the autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy phenotype.
Halonen M.; Eskelin P.; Myhre A.-G.; Perheentupa J.; Husebye E.S.; Kaempe O.; Rorsman F.; Peltonen L.; Ulmanen I.; Partanen J.;
J. Clin. Endocrinol. Metab. 87:2568-2574(2002)
Cited for: VARIANTS APS1 VAL-21; CYS-85 AND TYR-311;

Dominant mutations in the autoimmune regulator AIRE are associated with common organ-specific autoimmune diseases.
Oftedal B.E.; Hellesen A.; Erichsen M.M.; Bratland E.; Vardi A.; Perheentupa J.; Kemp E.H.; Fiskerstrand T.; Viken M.K.; Weetman A.P.; Fleishman S.J.; Banka S.; Newman W.G.; Sewell W.A.; Sozaeva L.S.; Zayats T.; Haugarvoll K.; Orlova E.M.; Haavik J.; Johansson S.; Knappskog P.M.; Loevaas K.; Wolff A.S.; Abramson J.; Husebye E.S.;
Immunity 42:1185-1196(2015)
Cited for: INVOLVEMENT IN APS1; FUNCTION; SUBCELLULAR LOCATION; VARIANTS APS1 PRO-28; CYS-90; MET-301; TYR-311 AND LEU-326; CHARACTERIZATION OF VARIANTS PRO-28; CYS-90; MET-301; TYR-311 AND LEU-326; MUTAGENESIS OF 28-LEU-LEU-29; LEU-97; ASP-297; ARG-303; ASP-312; CYS-446 AND ARG-471; VARIANTS LYS-298; TRP-299; TYR-302; GLN-303; TRP-303; SER-305; ARG-306; MET-309; GLN-316; TRP-316; PRO-319; GLN-328; TRP-328; ARG-332 AND ALA-484; CHARACTERIZATION OF VARIANTS LYS-298; TYR-302; SER-305 AND GLN-328;

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.