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Gene Expresion Essay

5233 words - 21 pages

1. DEFINATION: Nuclear receptors are a superfamily of ligand activated transcription factors that modulate specific gene expression.
Currently there are 100 nuclear receptor are identified[1].
2. INTRODUCTION: In the field of molecular biology, nuclear receptors are a class of proteins found within other molecules. In response, these receptors work in concert with other proteins to regulate the expression of specific genes thereby controlling the development, homeostasis, and metabolism of the organism.
Nuclear receptors have the ability to directly bind to DNA and regulate the expression of adjacent genes, hence these receptors are classified as transcription factors. The regulation of ...view middle of the document...

Some of these receptors such as FXR, LXR, and PPAR bind a number of metabolic intermediates such as fatty acids, bile acids and/or sterols with relatively low affinity. These receptors hence may function as metabolic sensors. Other nuclear receptors, such as CAR and PXR appear to function as xenobiotic sensors up-regulating the expression of cytochrome P450 enzymes that metabolize these xenobiotics[5].
[pic] [FIGURE-1]
Structural Organization ofNuclearReceptors
Top – Schematic 1D amino acid sequence of a nuclear receptor.
Bottom – 3D structures of the DBD (bound to DNA) and LBD (bound to hormone) regions of the nuclear receptor. The structures shown are of the estrogen receptor. Experimental structures of N-terminal domain (A/B), hinge region (D), and C-terminal domain (E) have not been determined therefore are represented by red, purple, and orange dashed lines respectively.
Nuclear receptors are modular in structure and contain the following domains:

• A-B) N-terminal regulatory domain: Contains the activation function 1 (AF-1) whose action is independent of the presence of ligand. The transcriptional activation of AF-1 is normally very weak, but it does synergize with AF-2 (see below) to produce a more robust upregulation of gene expression. The A-B domain is highly variable in sequence between various nuclear receptors.

• C) DNA-binding domain (DBD): Highly conserved domain containing two zinc fingers which binds to specific sequences of DNA called hormone response elements (HRE).

• D) Hinge region: Thought to be a flexible domain which connects the DBD with the LBD. Influences intracellular trafficking and subcellular distribution.

• E) Ligand binding domain (LBD): Moderately conserved in sequence and highly conserved in structure between the various nuclear receptors.

• in which three anti parallel alpha helices (the "sandwich filling") are The structure of the LBD is referred to as an alpha helical sandwich fold (SCOP flanked by two alpha helices on one side and three on the other (the "bread"). The ligand binding cavity is within the interior of the LBD and just below three anti parallel alpha helical sandwich "filling". Along with the DBD, the LBD contributes to the dimerization interface of the receptor and in addition, binds coactivator and corepressor proteins. Contains the activation function 2 (AF-2) whose action is dependent on the presence of bound ligand.

• F) C-terminal domain: Variable in sequence between various nuclear receptors [7-12].

4. MECHANISM OF ACTION:

[pic]
[FIGURE-2]
Mechanism nuclear receptor action: This figure depicts the mechanism of a class II nuclear receptor (NR) which, regardless of ligand binding status is located in the nucleus bound to DNA. For the purpose of illustration, the nuclear receptor shown here is the thyroid hormone receptor (TR) heterodimerized to the RXR. In the absence of ligand,...

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