NCOA1 is the firstly cloned nuclear hormone receptor co-activator (Onate et al., 1995; Xu et al., 2009). The canonical transcript (ENST00000348332.7; NM_003743) includes 21 exons, 19 of which are encoded (GRCh38.p10; http://www.ensembl.org).

Four alternatively spliced isoforms of NCOA1 have firstly been illustrated (Kamei et al., 1996). Compared to NCOA1a, NCOA1b lacks the N-termial domain, and NCOA1c, d and e have unique C-terminal sequences. NCOA1a and b have been shown to display diverse abilities to increase the estrogen receptor α ( ESR1 (Erα)) activity in cell lines (Kalkhoven et al., 1998; Xu et al., 2009). According to Ensembl database, there are eleven different transcripts of NCOA1 gene. Six of these transcripts encode two different proteins while five of them cannot encode protein. Lengths of the transcripts vary between 7405-501 bp (GRCh38.p10; http://www.ensembl.org).

NCOA1 gene encodes two similar proteins. The length of the canonical protein is 1441 amino acids with a molecular mass of 156,757 Da (UniPort ID: Q15788) and the length of the second protein is 1248 amino acids with a molecular mass of 135,621 Da (UniProt ID: B5MCN7). Like the other SRCs (NCOA2 and NCOA3 (SRC-2 and 3)), NCOA1 consists of three structural domains. The protein-protein interaction is performed via an N-terminal basic helix-loop-helix-Per/ARNT/Sim (bHLH-PAS) domain. This domain is highly conserved amongst p160 SRC family and promotes interaction with the transcription factors, such as myogenin, MEF-2C and TEF. The central domain which consists of LXXLL motifs forming amphipathic alpha-helices supports interaction with nuclear hormone receptors. The C-terminal domain includes two transcription activation domains, AD1 and AD2. AD1 binds and recruits CREBBP and EP300 (CBP and p300 histone acetyltransferase (HAT)) for chromatin remodeling, which is critical for SRC-mediated transcriptional activation. AD2 interacts with histone methyltransferases, coactivator-associated arginine methyltransferase 1 ( CARM1) and protein arginine methyltransferases ( PRMT1). The C-terminus of NCOA1, like SRC-3, also includes a HAT activity domain (Torchia et al., 1997; Xu et al., 2009).

Chen et al. showed that NCOA1 was expressed in placental labyrinth (Chen et al., 2010). According to The Human Protein Atlas database, NCOA1 is highly expressed in cerebral cortex, hippocampus, cerebellum, thyroid gland, parathyroid gland, adrenal gland, lymph node, nasopharynx, bronchus, gallbladder, pancreas, oral mucosa, esophagus, stomach, duodenum, small intestine, colon, rectum, kidney, urinary bladder, testis, fallopian tube, breast, vagina and placenta.

NCOA1 is synthesized in cytoplasm and imported into nucleus, and localized as speckles in both cytoplasm and nucleus. Localization to nucleus is performed thanks to nuclear localization signal located in between amino acids 18 and 36. After it display its function, it is exported to cytoplasm back, which is thought to inhibition of hormone action via NCOA1 degradation in cytoplasm. Exportation to cytoplasm back occurs owing to nuclear export signal located between amino acids 990 and 1038 (Amazit et al., 2003).

NCOA1 increases the transcriptional activities of nuclear hormone receptors in a hormone-dependent manner. In addition to nuclear hormone receptors, NCOA1 and other SRCs are the coactivators of other transcription factors including NF-kB, Smads, E2F1, STATs, HIF1A, TP53, RB1, ETV4 (polyoma enhancer activator 3 (PEA3)) and ETS2. They support gene transcription by interacting with kinases, ubiquitin/sumoligases, phosphatases, histone acetyltransferases and histone methyltransferases (Qin et al., 2009; McBryan et al., 2012; Xu et al., 2009). Due to its role in transcription, NCOA1 and other SRCs have a role in different physiological functions, including cell cycle and energy metabolism. NCOA1 itself is critical for organ physiology. It has been showed that NCOA1 deficiency strongly influenced mice reproductive organ development (Xu et al., 1998). NCOA1-/- mice also displayed partial resistance to sex steroids and thyroid hormone (Weiss et al., 1999; Kamiya et al., 2003). NCOA1 is also important for the gluconeogenesis. In liver, it is a coactivator of CEBPA (CEBPα) which regulates the pyruvate carboxylase gene, the limiting enzyme for gluconeogenesis, together with PPARG (PPARγ). Activated PPARγ recruits NCOA1 and other coregulators, such as PGC-1 and CBP/p300 in brown fat, and deficiency in NCOA1 results in drawbacks in activity of PGC-1. This drawback further decreases energy expenditure and causes obesity with high fat diet (Xu et al., 2009).
Phosphorylation is critical in the functioning of SRC family proteins. Phosphorylation of SRCs alters their affinities for certain nuclear hormone receptors (Lopez et al., 2001; Rowan et al., 2000; Wu et al., 2004; Giamas et al., 2009). Moreover, phosphorylation by different kinases via different Ser/Thr amino acids results in determination of down-stream processes. NCOA1 could be phosphorylated by EGF, IL6, CAMP, CCNA2 (cyclin A2)/ CDK2, CDK1 and MAPK. Cyclin A2/Cdk2- and EGF-mediated phosphorylation increases progesterone receptor ( PGR)-dependent transcription while IL-6-induced phosphorylation supports androgen receptor ( AR)-dependent transcription via ligand independency. Additionally, cAMP-mediated phosphorylation of NCOA1 recruits p300 and CBP and activates PR-dependent transcription via ligand independency and MAPK-induced NCOA1 phosphorylation enhances the affinity of NCOA1 towards AR in prostate cancer cells (Rowan et al., 2000; Wu et al., 2004; Giamas et al., 2009; Ueda et al., 2002; Rowan et al., 2000b; Gregory et al., 2004; Xu et al., 2009; Moore and Weigel, 2011). In addition to phosphorylation, sumoylation of NCOA1 at Lys731 and Lys774 by SUMO1 was showed to increase the interaction between PR and NCOA1, and upregulate PR-mediated transcription (Chauchereau et al., 2003).
In hormone-dependent progesterone receptor activity, NCOA1 was shown to be down-regulated in hormone-dependent manner like PR to activate the transcription of target genes. NCOA1 down-regulation was illustrated to be predominantly in cytoplasmic compartment via proteasomal degradation and the down-regulation of NCOA1 together with PR is critical for the regulation of transcription (Amazit et al., 2011).
The interaction of NCOA1 with PR to regulate gene expression was partly underlined in a study where KAT7 (HBO1) (a member of the MYST acetylase family) was illustrated to modulate interaction of NCOA1 and PR in a hormone-dependent manner in human testis cell line, CV1 and human embryonic kidney cell line, HEK293 (Georgiakaki et al., 2006).
NCOA1 has been shown to affect developmental processes. NCOA1 and NCOA3 double knockout mice died at early embryonic stage while single knockout mice lived normally, pointing a cooperative role of NCOA1 and NCOA2 in embryo survival. Moreover, morphologies of labyrinths of NCOA1 (together with NCOA3) knockout mice embryos were abnormal via altered expression of genes responsible for placental morphogenesis, and glucose metabolism (Chen et al., 2010).
Baldwin et al. showed that high-risk human papillomavirus type 16 (HPV16) E7 oncoprotein affected the localization and function of NCOA1; relocalized NCOA1 into cytoplasm and decreased NCOA1-mediated gene expression and NCOA1-dependent histone acetyltransferase (HAT) activity in vivo and in vitro in cervical cancer cell line, HeLa (Baldwin et al., 2006).
NCOA1 has also been linked to glucose metabolism. Under glucose deprivation, NCOA1 was proved to stabilize 26S proteasome and affect the expression of complex I of the mitochondrial electron transport chain (Motamed et al., 2014).

NCOA2 (SRC-2, TIF2 or GRIP1) and NCOA3 (SRC-3, p/CIP, RAC3, AIB1, ACTR or TRAM-1) are homologous to NCOA1 and these three proteins are included in a family, called p160 SRC (Torchia et al., 1997; Xu et al., 2009).

A single nucleotide polymorphism (SNP) in NCOA1 (rs1804645; P1272S) was demonstrated to decrease ER activation while it increase protein life-time via blocking phosphorylation by glycogen synthase 3 ( GSK3B) in bone. Moreover, this SNP was linked to a decrease in hip and lumbar bone mineral density in women receiving tamoxifen (Hartmaier et al., 2011).
Another SNP in NCOA1 (rs7948087) was associated to multiple myeloma phenotype in Chinese Han population (Peng et al., 2017).
Four different SNPs in NCOA1 (rs11894248, rs17791703, rs7572475 and rs9309308) were linked to Kawasaki disease in Taiwanese people (Chen et al., 2014).
Two chromosomal rearrangements affecting NCOA1 in patients with sarcoma subtypes were identified. In one study, a novel t(2;2)(q35;p23) translocation generating PAX3/NCOA1 fusion protein has been shown (Wachtel et al., 2004). Similar fusion protein was proved to be a result of inv(2)(q35p23) mutation (Huang et al., 2016).
According to ClinVar database, huge chromosomal deletions and duplications in regions including NCOA1 gene have been submitted. These mutations showed to be pathogenic, benign or with uncertain significance.