nuclear receptor coactivator 3; NCoA-3; thyroid hormone receptor activator molecule 1; TRAM-1; receptor-associated coactivator 3; RAC-3; amplified in breast cancer 1 protein; AIB-1; steroid receptor coactivator protein 3; SRC-3; CBP-interacting protein; pCIP; ACTR; class E basic helix-loop-helix protein 42; bHLHe42 (NCOA3, AIB1, BHLHE42, RAC3, TRAM1)

Function

• nuclear receptor coactivator
• binds nuclear receptors & stimulates the transcriptional activities (hormone-dependent)
• role in creating a multisubunit coactivator complex, which probably acts via remodeling of chromatin
• role in coactivation of different nuclear receptors, including
  • steroid hormone receptors (GR & ER)
  • retinoid receptors (RAR & RXR)
  • thyroid hormone receptors (erbA)
  • vitamin D3 receptor (VDR)
  • prostanoid receptors (PPARs)
• histone acetyltransferase activity
• role in coactivation of the NF-kappa-B pathway via its interaction with the NFKB1 subunit.
• interacts with PSMB9
• coactivator activity on nuclear receptors & NF-kappa-B pathways is enhanced by various hormones, & TNF, respectively
• TNF stimulation probably enhances phosphorylation, which in turn activates coactivator function
• in contrast, acetylation by CREBBP apparently suppresses coactivation of target genes by disrupting its association with nuclear receptors
• acetylated by CREBBP
• acetylation occurs in the RID domain, & disrupts interaction with nuclear receptors
• methylated by CARM1 (putative)
• phosphorylated by IKK complex
• interacts with CARM1 (putative)
• present in a complex containing NCOA2, IKKA, IKKB, IKBKG & the histone acetyltransferase protein CREBBP
• interacts with CASP8AP2, NR3C1 & PCAF
• interacts with ATAD2; interaction is enhanced by estradiol

Structure

• contains three Leu-Xaa-Xaa-Leu-Leu (LXXLL) motifs
  • motifs 1 & 2 are essential for the association with nuclear receptors, & constitute the RID domain (receptor-interacting domain)
• belongs to the SRC/p160 nuclear receptor coactivator family
• contains 1 basic helix-loop-helix (bHLH) domain
• contains 1 PAS (PER-ARNT-SIM) domain

Compartment

• cytoplasm, nucleus
• mainly cytoplasmic & weakly nuclear
• upon TNF activation & subsequent phosphorylation, it translocates from the cytoplasm to the nucleus

Alternative splicing

• named isoforms=5
• additional isoforms seem to exist

Expression

• widely expressed
• high expression in heart, skeletal muscle, pancreas & placenta
• low expression in brain
• very low expression in lung, liver & kidney

Pathology

• NCOA3 is frequently amplified or overexpressed in breast cancer & ovarian cancer

Polymorphism

• the length of the poly-Gln region is polymorphic in the normal population

More general terms

• nuclear (steroid) receptor coactivator (NRC, SRC, NCoA)
• acetyltransferase
• DNA-binding protein
• phosphoprotein

Additional terms

• nuclear hormone receptor family

Database

• Entrez gene: http://www.ncbi.nlm.nih.gov/sites/entrez?db=gene&cmd=Retrieve&dopt=Graphics&list_uids=8202
• Kegg: http://www.genome.jp/dbget-bin/www_bget?hsa:8202
• OMIM: https://mirror.omim.org/entry/601937
• UniProt: http://www.uniprot.org/uniprot/Q9Y6Q9.html