Amino terminal domain

Steroid receptors contain activation functions 1 and 2 (AF1 and AF2) at their NH2-and COOH- terminal regions. In contrast to other steroid hormone receptors that contain a strong transactivation function at their COOH-terminus, the COOH-terminal AF2 domain in AR has a weak transactivation potential. Most of the transactivation function of the AR is carried out by the NH2-terminal domain of the receptor (Jenster etal. 1995; Poukka etal. 2000a). The mechanism of transcriptional activation by the NH2-terminus is not quite understood but it is thought that the NH2-terminus may represent a surface for recruitment of coregulators. Consistent with this idea, several coactivators including SRC-1, GRIP-1 and CBP have been shown to interact with the NH2-terminus (Ikonen etal. 1997; Alen etal. 1999; Bevan etal. 1999; Ma etal. 1999). While most of the entire NH2-terminus (amino acids 1-494) is required for full activity of the full length receptor, a core that contributes to 50% of its activity is located between residues 101 and 360 and this region has been termed t 1. However, in the absence of the HBD, a different region termed t5 (residues 370 to 494) mediates transactivation (Jenster etal. 1995) (Fig. 2.2). The AF-1 at the NH2-terminus has also been separated into AF1a (amino acids 154-167) and AF-1b (amino acids 259-459) both of which are required for full transactivational activity (Chamberlain etal. 1996). NH2-terminal residues of the AR (142-485) have been shown to activate a minimal promoter construct with the transcription factor TFIIF and the TATA binding protein (TBP), suggesting

Functional domain structure of the human androgen receptor

Schematic diagram of the AR showing the N-terminal AF1 activation domain with two independent transactivation functions, t 1 and t5, DNA binding domain (DBD) in the middle of the molecule, hinge region (HR) and hormone binding domain (HBD) with a weak hormone-dependent transactivation function at the COOH-terminus of the receptor. The signal responsible for nuclear import is located at the junction of the DBD and hinge region.

Functional domain structure of the human androgen receptor

Schematic diagram of the AR showing the N-terminal AF1 activation domain with two independent transactivation functions, t 1 and t5, DNA binding domain (DBD) in the middle of the molecule, hinge region (HR) and hormone binding domain (HBD) with a weak hormone-dependent transactivation function at the COOH-terminus of the receptor. The signal responsible for nuclear import is located at the junction of the DBD and hinge region.

a direct contact of the NH2-terminus with the general transcriptional machinery (McEwan and Gustafsson 1997).

The amino terminus of the AR contains a CAG repeat stretch. Sequence analysis of the AR in a variety of species have shown that the amino-terminal CAG repeat increases exponentially with decreasing evolutionary distance from the human (Choong and Wilson 1998). For example, the number of CAG triplets is about 22 in humans, while in the prosimian lemur, a more distant primate species in evolutionary terms, it remains at 4 (Choong and Wilson 1998). The expansion of triplet motifs in the AR and their polymorphic nature in great apes which is not present in lower species indicate that differences in cellular factors or genetic changes could have led to an instable AR. The remaining amino acids residues in the AR extending from 1-53 and 360-429 including a polyproline stretch are completely conserved among primates. The high conservation of these other sequences might play an important role in the NH2-/COOH- interactions which are so crucial for transactivation by the androgen receptor.

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