Tyrosine protein kinases using the insulin receptor as an example
The insulin receptor is a classic example of a catalytic receptor. It is a tetramer consisting of four subunits:
- Two $\alpha$-subunits: located extracellularly. Their N-terminal domains form the hormone-binding site.
- Two $\beta$-subunits: span the membrane (transmembrane domains). Their intracellular portion contains tyrosine residues and possesses catalytic (tyrosine kinase) activity.
When an insulin molecule binds to the $\alpha$-subunits, cooperative conformational changes occur. This activates the tyrosine kinase within the $\beta$-subunits. Transautophosphorylation begins: one $\beta$-subunit phosphorylates the other at tyrosine residues using high-energy ATP bonds (ATP is converted to ADP).
As a result, the charge, conformation, and substrate specificity of the enzyme change. The active receptor phosphorylates the insulin receptor substrate (IRS-1). This protein acts as a key adapter. If its structure is impaired, signal transduction is blocked. Next, IRS-1 binds to the enzyme PI3 kinase, leading to the formation of PIP3 and activation of protein kinase B (Akt/PKB).
Cellular effects of insulin receptor activation
The initiated intracellular cascade leads to three main groups of effects:
- Metabolic regulation (enzyme activation)
Phosphodiesterase is activated, which converts cAMP into AMP and cGMP into GMP, lowering the levels of these secondary messengers (this inhibits glycogen and lipid breakdown). Phosphoprotein phosphatases are also activated, which dephosphorylate metabolic enzymes (for example, they activate glycogen synthase to store glucose). To turn off the signal itself, a specific tyrosine protein phosphatase operates—it dephosphorylates the receptor's $\beta$-subunits.
- Glucose transport
In insulin-dependent tissues (muscle and adipose tissue), the translocation of GLUT-4 transporter proteins from the cytosol to the plasma membrane is stimulated. This ensures the influx of glucose into the cell.
- Genomic effect
The signal is transmitted to nuclear regulatory proteins and transcription factors. Repression of synthesis and degradation of certain enzymes occur, along with the induction of anabolic enzyme synthesis (protein, lipid, and glycogen synthesis).
Growth factor receptors
In the inactive state, such receptors are represented by a single polypeptide chain. It consists of a glycosylated extracellular domain, a transmembrane domain ($\alpha$-helix), and a cytoplasmic domain with protein kinase activity.
Upon binding a primary messenger (growth factor), the receptors pair up, forming dimers. Dimerization activates the intracellular domains, followed by trans-autophosphorylation at serine, threonine, or tyrosine residues. The resulting phosphorylated residues serve as binding sites for specific cytosolic proteins, triggering a further protein kinase cascade.
Receptors with guanylyl cyclase activity
These receptors represent a membrane-bound guanylyl cyclase (GC)—a transmembrane glycoprotein. The extracellular domain binds the hormone, while the intracellular domain exhibits catalytic activity.
A physiological example of such a ligand is the atrial natriuretic peptide (ANP), which regulates fluid homeostasis in the body.
Signal transduction mechanism:
- Hormone attachment activates guanylyl cyclase.
- The enzyme catalyzes the formation of cyclic guanosine-3',5'-monophosphate (cGMP) from GTP.
- cGMP molecules bind to the regulatory sites of protein kinase G (PKG). Exactly 4 cGMP molecules are required to alter the conformation and activate this enzyme.
- Active PKG phosphorylates specific cytosolic proteins and enzymes, transferring a phosphate group from ATP to the target protein.
To remember the structure of the insulin receptor, imagine an antenna: the α-subunits are located outside and "catch" the signal (insulin), while the β-subunits pierce the wall (membrane) and conduct the reaction inside the house.
Class and exam questions
How does the "turn-off" of the signal from the insulin receptor occur?
The process is halted thanks to tyrosine protein phosphatase. This enzyme dephosphorylates the $\beta$-subunits of the insulin receptor itself, terminating further signal transduction.
What is trans-autophosphorylation?
This is a reaction in which one subunit in the activated receptor phosphorylates the other (neighboring) one, and vice versa. This is characteristic of insulin and growth factor receptors.
How many cGMP molecules are needed to activate protein kinase G?
The binding of four cGMP molecules to its regulatory sites is required for the conformational change and complete transition of protein kinase G to the active state.
What else to study on this topic
- The role of the PI3 kinase enzyme and the formation of PIP3 in the signaling cascade.
- The detailed mechanism of GLUT-4 transporter translocation into the plasma membrane.
- The interaction of kinases and phosphoprotein phosphatases in the regulation of metabolism (antagonism).
- Physiological mechanisms of fluid homeostasis regulation using ANP.
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