Transcription Factors And Regulators Proteins

 Transcription Factors And Regulators Proteins Background

Transcription factors

Transcription factors (TFs) are cell regulatory proteins that facilitate proper cell function by controlling gene expression in response to intracellular and extracellular stimuli. TFs have two domains: i) the DNA binding domain that binds specific sites of chromosomal DNA, thereby directing which gene(s) will be controlled; ii) the trans-activating domain that interacts with other proteins and co-factors initiating the required changes in gene expression. TFs regulate proper cell function across the range of cell process from development to differentiation.

Transcription factors structure

Both the DNA sequence and TF structure plays important role in specific interaction of DNA and TF. Binding of the TF to the DNA changes the structure of the DNA and altering the accessibility of the region to RNA polymerase, leading to gene activation or repression. Structural studies of TFs have shown that there are a number of common, TF structural motifs, including helix-turn helix, helix-loop-helix, zinc finger, and leucine zipper. Common among all of these motifs is the placement of an α-helix of the TF into the major groove of the DNA structure, with additional affinity provided by hydrogen bonding and Van der Waals interactions between the amino acids and the nucleotide bases.

Helix-turn-helix (HTH) was the first transcription factor motif discovered. As the name indicates, this structure has an α-helix, a turn that stabilizes the protein structure, and a second α-helix. HTH motifs are not separate, stable domains; rather they are always part of larger DNA binding proteins. This motif usually binds as dimers and occurs in many DNA binding proteins such as Lac repressor, 434 repressor, or Trp repressor. Although the primary DNA-protein interactions occur between residues in the protein’s “recognition helix” and bases in the DNA major groove, it has been shown that other parts of the protein also have significant roles in recognition of the target.

Helix-loop-helix motifs (HLH) of transcription factors have two α-helices that mediate dimerization and a basic region that interact with DNA. These two α-helices are connected by a loop and one helix is bigger than the other helix. Bigger helix is typically the one that has basic region to bind consensus sequence called E-box. Sequence of E-box is characterized as CANNTG. HLH is primarily found in developmental genes such as MyoD and HIF-1.

Zinc finger motifs contain an antiparallel β-sheet and α-helix. This family of proteins usually contains the repeat of sequence pattern Cys-X2or4-Cys-X12-His-X3-5-His. Zinc ions are chelated by the two cysteines in the β-sheet region and two histidines in the α-helix region of protein.

Leucine zipper TFs contain heptad repeats of leucines in a 30-40 amino-acid sequence. This type of protein usually has two domains, the leucine zipper domain and a basic region. The leucine zipper domains form two α-helices and stabilize the protein with hydrophobic interactions, while the basic region contains amino acids that bind to DNA.

Transcription factors signaling

The activities of TFs are controlled by extracellular and intracellular signaling pathways resulting in the activation of transcription factors, either by transcription and translation of new TFs or by post-translational modification of Latent TFs, and their internalization into cellular nucleus. Latent TFs in the cytoplasm can be activated, for example, by tyrosine (e.g Stat) or serine (e.g c-Jun) phosphorylation. The phosphorylated proteins are then bound by importin, which translocates the TFs to the nucleus (e.g NF-κB). Nuclear TFs can be activated by phosphorylation following translocation of kinases from the cytoplasm to nucleus (e.g ETS). Additionally, most TFs require binding to other TFs or cofactors for gene expression to occur. For example, in Wnt signaling pathway, TCF/LEF transcription factors need bcatenin to activate the transcription. TCF/LEF transcription factors lack the trans activating domains, thus, require another factor to start the recruitment of RNA polymerase.

TF signaling networks are extraordinarily complex. Any one TF can respond to a variety of stimuli; additionally, multiple TFs are typically activated by any one stimulus. Thus, the profile of active TFs is complex and constantly changing. Aberrant TF activity results in improper cell function and can lead to disease (e.g., cancer). Therefore, monitoring of TF function is valuable for understanding biological processes and can support medical diagnoses and the development of novel therapeutics.