Signal transduction proteins can be generally divided into two classes: intracellular and extracellular receptors.
Extracellular receptors are integrated transmembrane proteins that make up the majority of receptors. They span the plasma membrane of the cell, with some of the receptors on the outside of the cell and the other on the inside of the cell. Signal transduction happens because the ligand binds to the outer region of the receptor (the ligand does not pass through the membrane). Ligand-receptor binding induces a change in the conformation of the inside part of the receptor, a process sometimes called "receptor activation. This results in activation of the enzymatic domain of the receptor or exposure of binding sites of other intracellular signaling proteins within the cell, ultimately allowing signals to propagate through the cytoplasm.
In eukaryotic cells, the majority of intracellular proteins activated by a ligand/receptor interaction possess an enzymatic activity, such as tyrosine kinase and phosphatases. Often such enzymes are covalently linked to the receptor. Some of them create second messengers such as cyclic AMP and IP3, the latter controlling the release of intracellular calcium stores into the cytoplasm. Other activated proteins interact with adaptor proteins that facilitate signaling protein interactions and coordination of signaling complexes necessary to respond to a particular stimulus. Both the enzyme and the adaptor protein react to a variety of second messenger molecules. Many adaptor proteins and enzymes are activated as part of signal transduction with a specialized protein domain that binds to a particular second messenger molecule. For example, calcium ions bind to the EF domain of calmodulin, allowing it to bind to and activate calmodulin-dependent kinases. PIP3 and different phosphoinositides have the same effect as the Pleckstrin homology domain of proteins such as the kinase protein AKT.
Tyrosine, Ser/Thr and Histidine-specific protein kinases
The receptor tyrosine kinase (RTK) is a transmembrane protein with an intracellular kinase domain and an extracellular domain that binds to a ligand; examples include growth factor receptors such as the insulin receptor. For signal transduction, RTK requires the formation of a dimer in the plasma membrane; The dimer is stabilized by a ligand that binds to the receptor. The interaction between the cytoplasmic domains stimulates autophosphorylation of tyrosine residues in the intracellular kinase domain of RTK, causing a conformational change. Subsequently, the kinase domain of the receptor is activated, triggering a phosphorylation signal cascade of downstream cytoplasmic molecules, promoting various cellular processes such as cell differentiation and metabolism. Most Ser/Thre and bispecific protein kinases are crucial for signal transduction, acting downstream of receptor tyrosine kinase, or as a membrane-embedded or cell-soluble form per se. The signal transduction process involves approximately 560 known protein kinases and pseudokinases, encoded by the human kinase group.
As is that the with GPCRs, proteins that bind GTP play a significant role in signal transduction from the activated RTK into the cell. In this case, the G proteins are members of the Ras, Rho, and Raf families, referred to put together as small G proteins. They act as molecular switches usually typically bound membranes by isoprenyl groups linked to their carboxyl ends. Upon activation, they assign proteins to specific membrane subdomains where they participate in signaling. Activated RTKs successively activate small G proteins that activate guanine nucleotide exchange factors like SOS1. Once activated, these exchange factors will activate more small G proteins, so amplifying the receptor's initial signal. The mutation of certain RTK genes, as with that of GPCRs, can lead to the expression of receptors that exist in a very activated state; such mutated genes might act as oncogenes. Histidine-specific protein kinases are structurally distinct from other protein kinases and are found in prokaryotes, fungi, and plants as part of a two-component signal transduction mechanism: a phosphate group from ATP is first added to a histidine residue in the kinase, then transferred to an aspartate residue on a receiver domain on a various protein or the kinase itself, thus activating the aspartate residue.
Intracellular receptors, such as nuclear receptors and cytoplasmic receptors, are soluble proteins localized within their respective areas. The typical ligands for nuclear receptors are non-polar hormones like the steroid hormones testosterone and progesterone and derivatives of vitamins A and D. To initiate signal transduction, the ligand should undergo the plasma membrane by passive diffusion. On binding with the receptor, the ligands pass through the nuclear membrane into the nucleus, altering gene expression.
Activated nuclear receptors attach to the DNA at receptor-specific hormone-responsive element (HRE) sequences, located in the promoter region of the genes activated by the hormone-receptor complex. Because of their gene transcriptional abilities, they are called inducers of gene expression. All hormones that act by regulating gene expression have two consequences in their mechanism of action; their effects are produced after a characteristic long time, and their action lasts for another long period of time, even if their concentration After being reduced to zero, the ligand is inactivated or terminated to bind to the receptor due to the relatively slow transition of most enzymes and proteins.
1. Manning G.; et al. he protein kinase complement of the human genome. Science. 2002,298 (5600): 1912–1934.
2. Reiterer V.; et al. Day of the dead: pseudokinases and pseudophosphatases in physiology and disease. Trends in Cell Biology. 2014, 24 (9): 489–505.
3. Wolanin PM.; et al. Histidine protein kinases: key signal transducers outside the animal kingdom. Genome Biology.2002,3 (10): REVIEWS3013.