Benutzer:Hoffmeier/Nukleärer Rezeptor

Die nukleären Rezeptoren (NR), sind intrazelluläre Rezeptoren und bilden eine Superfamilie.

Typen

Manglesdorf et al. (2) proposed four categories of nuclear receptors in which Class 1 receptors include the known steroid hormone receptors, which function as homodimers binding to half-site RE inverted repeats. Class 2 receptors exist as heterodimers with RXR receptor partners and function in a ligand-dependent manner. The second two classes include orphan receptors, which function as homodimers binding to direct RE repeats (Class 3) or monomers binding to single site REs (Class 4).

Typ I

Steroidhormonrezeptoren

• Androgen-Rezeptor
• Estrogen-Rezeptor
• Progesteron-Rezeptor
• Glucocorticoid-Receptor
• Mineralocorticoid-Receptor

Typ II

• Vitamin A Rezeptor
• Vitamin-D-Rezeptor
• Retinoid Rezeptor
• Thyroidhormon Rezeptor

Structure

Structural Organization of Nuclear Receptors
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) (InterPro: IPR001628 (englisch)): Highly conserved domain containing two zinc fingers (Vorlage:SCOP) 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) (InterPro: IPR000536 (englisch)): Moderately conserved in sequence and highly conserved in structure between the various nuclear receptors. The structure of the LBD is referred to as an alpha helical sandwich fold (Vorlage:SCOP) in which three anti parallel alpha helices (the "sandwich filling") are 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.

Structure

Steroid hormone receptors share a common structure of four units that are functionally homologous, so-called "domains":

1. Variable domain: It begins at the N-terminal and is the most variable domain between the different receptors.
2. DNA binding domain: This centrally located highly conserved DNA binding domain (DBD) consists of two non-repetitive globular motifs (PDB: 1HCQ) where zinc is coordinated with four cysteine and no histidine residues. Their secondary and tertiary structure is distinct from that of classic zinc fingers. This region controls which gene will be activated. On DNA it interacts with the hormone response element (HRE).
3. Hinge region: This area controls the movement of the receptor to the nucleus.
4. Hormone binding domain: The moderately conserved ligand-binding domain (LBD) can include a nuclear localization signal, amino-acid sequences capable of binding chaperones and parts of dimerization interfaces. Such receptors are closely related to chaperones (namely heat shock proteins hsp90 and hsp56), which are required to maintain their inactive (but receptive) cytoplasmic conformation. At the end of this domain is the C-terminal. The terminal connects the molecule to its pair in the homodimer or heterodimer. It may affect the magnitude of the response.

Only type I receptors have a heat shock protein (hsp) associated with the inactive receptor that will be released when the receptor interacts with the ligand. Type I receptors may be found in homodimer or heterodimer forms. Type II receptors have no hsp, and in contrast to the classical type I receptor are located in the cell nucleus.

There is some evidence that certain steroid hormone receptors can extend through lipid bilayer membranes at the surface of cells and might be able to interact with hormones that remain outside of cells.

Steroid hormone receptors can also function outside of the nucleus and couple to cytoplasmic signal transduction proteins such as PI3k and Akt kinase.