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autoimmune regulator; autoimmune polyendocrinopathy candidiasis ectodermal dystrophy protein; APECED protein (AIRE, APECED)
Function:
- transcriptional regulator that binds to DNA as a dimer or as a tetramer
- binds to G-doublets in an A/T-rich environment
- the preferred motif is a tandem repeat of 5'-. ATTGGTTA-3' combined with a 5'-TTATTA-3' box
- binds to nucleosomes (putative)
- binds to chromatin & interacts selectively with histone H3 that is not methylated at Lys-4, not phosphorylated at Thr-3 & not methylated at Arg-2
- functions as a sensor of histone H3 modifications that are important for the epigenetic regulation of gene expression
- functions as a transcriptional activator & promotes expression of otherwise tissue-specific self-antigens in the thymus, which is important for self tolerance & the avoidance of autoimmune reactions
- phosphorylated
- phosphorylation could trigger oligomerization
- homodimer & homotetramer
- interacts with CREBBP
- interacts preferentially with histone H3 that is not methylated at Lys-4
- binds with lower affinity to histone H3 that is monomethylated at Lys-4
- trimethylation of histone H3 at Lys-4 or phosphorylation at Thr-3 abolish the interaction
- binds with lower affinity to histone H3 that is acetylated at Lys-4, or that is acetylated at Lys-9 or trimethylated at Lys-9
- binds histone H3 that is dimethylated at Arg-2 with very low affinity
Structure:
- the L-X-X-L-L repeats may be implicated in binding to nuclear receptors
- the HSR domain is required for localization on tubular structures (N-terminal part) & for homodimerization
- interacts via the first PHD domain with the N-terminus of histone H3 that is not methylated at Lys-4
- disruption of the first PHD domain leads to reduced transcriptional activity & to localization mainly in the cytoplasm in small granules
- the PHD Zn+2 fingers are necessary for transactivation capacity; however, other regions also modulate this function
- contains 1 HSR domain
- contains 2 PHD-type Zn+2 fingers
- contains 1 SAND domain
Compartment:
- nucleus, cytoplasm
- associated with tubular structures & in discrete nuclear dots resembling ND10 nuclear bodies
- may shuttle between nucleus & cytoplasm
Alternative splicing:
- named isoforms=3
- additional isoforms seem to exist
Expression:
- widely expressed
- expressed at higher level thymus
- medullary epithelial cells
- monocyte-dendritic cells
- expressed at higher level in pancreas, adrenal cortex & testis
- expressed at low level in spleen, fetal liver & lymph nodes
- isoform 2 & isoform 3 seem to be less frequently expressed than isoform 1, if at all
Pathology:
- mutations associated with autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy
- most of the mutations alter the nucleus-cytoplasm distribution of AIRE & disturb its association with nuclear dots & cytoplasmic filaments
- most of the mutations also decrease transactivation of the protein
- the HSR domain is responsible for the homomultimerization activity of AIRE
- all the missense mutations of the HSR domain & the SAND domains decrease homomultimerization, but those in other domains do not
- the AIRE protein is present in soluble HMW complexes
- mutations in the HSR domain & deletion of PHD Zn+2 fingers disturb the formation of these HMW complexes
Related
AIRE gene mutation
General
DNA-binding protein
transcription factor, not classified
Properties
SIZE: entity length = 545 aa
MW = 58 kD
COMPARTMENT: cytoplasm
cell nucleus
MOTIF: HSR {1-105}
MOTIF: LXXLL motif 1 {7-11}
LXXLL motif 2 {63-67}
SAND {181-280}
domain {295-298}
Zn finger PHD-type
NAME: Zn finger PHD-type
SITE: 296-343
EFFECTOR-BOUND: Zn+2
MOTIF: domain {304-312}
domain {331-335}
LXXLL motif 3 {414-418}
Zn finger PHD-type
NAME: Zn finger PHD-type
SITE: 434-475
EFFECTOR-BOUND: Zn+2
LXXLL motif 4 {516-520}
Database Correlations
OMIM correlations
MORBIDMAP 607358
UniProt O43918
PFAM correlations
Entrez Gene 326
Kegg hsa:326
References
- UniProt :accession O43918
- AIREbase; Note: AIRE mutation db
http://bioinf.uta.fi/AIREbase/
- GeneReviews
http://www.ncbi.nlm.nih.gov/sites/genetests/lab/gene/AIRE