Nuclear activation function

SHRs are built in a modular structure with similar structure elements. They contain a DNA-binding domain (DBD), a hinge region with a nuclear location signal (NLS), a ligand-binding domain (LBD) and several transcriptional activation functions (Fig. 1). 

The diversity of nuclear receptor systems is also demonstrated by the fact that orphan receptors exist, which exercise a constitutive repressive or activating function independent of ligand. 

The R-Smad proteins interact with type I receptor and co-regulatory Smad (co-Smad) proteins in the signal cascade by virtue of conserved MH1 and MH2 domains at their N- and C-termini, which are separated by a variable, non-conserved region. These domains possess DNA binding and transcriptional activation functions, respectively. The inactive MH1 domain interacts with the MH2 domain in an auto-inhibitory manner. However, once C-terminal phosphorylation by the type I receptor occurs, this inhibitory association is alleviated and the R-Smad is then able to interact with its appropriate co-Smad. The phosphorylated R-Smad/co-Smad complex is capable of translocation to the cell nucleus where, in coordination with nuclear factors, it is able to exert its transcriptional activation function. 

Apopa PL, He X, Ma Q. 2008. Phosphorylation of Nrf2 in the transcription activation domain by casein kinase 2 (CK2) is critical for the nuclear translocation and transcription activation function of Nrf2 in IMR-32 neuroblastoma cells. J Biochem Mol Toxicol 22 63-76. 

Burris TP, Pelton PD, Zhou L, et al. A novel method for analysis of nuclear receptor function at natural promoters peroxisome proliferator-activated receptor y agonist actions on a P2 gene expression detected using branched DNA messenger RNA quantitation. Mol Endocrinol 1999 13 410—417. 

Wammark A, et al. Activation functions 1 and 2 of nuclear receptors molecular strategies for transcriptional activation. Mol. Endocrinol. 2003 17 1901-1909. 

Desclozeaux M, et al. Phosphorylation and intramolecular stabilization of the ligand binding domain in the nuclear receptor steroidogenic factor 1. Mol. CeU Biol. 2002 22 7193-7203. Wansa KD, Harris JM, Muscat GE. The activation function-1 domain of Nur77/NR4A1 mediates trans-activation, cell specificity, and coactivator recruitment. J. Biol. Chem. 2002 277 33001-33011. 

PNRC Two proline-rich nuclear receptor coregulatory proteins (PNRC1 and PNRC2) were cloned from a mammary gland cDNA library (97,98). These proteins are relatively small, with molecular weights of 16 kDa and 35 kDa, respectively. Both PNRCs interacted with hormone receptors in a ligand-dependent manner, mediated by an activation function domain that contains an NR box-like... 

Voegel JJ, Heine MJ, Zechei C, Chambon P, Gronemeyer H. 1996. TIF2, apl60 kDa transcriptional mediator for the ligand-dependent activation function AF-2 of nuclear receptors. EMBO, J. 15 3667-75... 

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