Here, we will discuss the definition, types, and examples of enzyme-linked receptors. We will also briefly discuss how enzyme-linked receptors, like the ones for insulin, initiate signal transduction.
Cell signaling and enzyme-linked receptors
Cell signaling is the process by which a cell responds to messages from its external environment through protein receptors.
A ligand is a molecule that can bind to another molecule. In cell signaling, the ligand binds to a receptor, which is a protein that is present inside or on the surface of the target cell.
There are two main types of cell receptors: internal and cell-surface receptors.
Internal receptors (also known as cytoplasmic or intracellular receptors) can be found in the cytoplasm. Internal receptors bind hydrophobic (or non-polar) ligands such as steroid hormones.
Cell-surface receptors span the plasma membrane, such that each receptor has extracellular, transmembrane, and cytoplasmic or intracellular regions. Ligands that bind with cell-surface receptors are not required to enter the cell. Instead, extracellular signals need to be converted into intracellular signals in a process called signal transduction.
Cell-surface receptors can be further classified into three categories based on the mechanism performed to convert the signal into a cellular response:
G-protein-coupled receptors are bound by a ligand, which activates a type of membrane protein known as G-protein, which then interacts with an ion channel or an enzyme in the plasma membrane.
Ion channel-linked receptors work by binding a ligand and then opening a channel across the plasma membrane that allows specific ions to pass through.
Enzyme-linked receptors bind a ligand, sending a signal through the membrane and activating the enzyme, which triggers a series of reactions, eventually leading to a response.
Location of enzyme-linked receptors
Like G-protein-coupled receptors, the extracellular domain of enzyme-linked receptors contains the signal's binding site, whereas the intracellular domain triggers the signal transduction pathway upon binding.
The cytosolic domain of the enzyme-linked receptor contains either intrinsic enzyme activity or directly interacts with an enzyme. An enzyme-linked receptor typically has only one component (compared to, say, G protein coupled receptors which have seven transmembrane segments).
Types of enzyme-linked receptors
Enzyme-linked receptors are the second biggest group of receptors following G protein coupled receptors. There are four types of enzyme-linked receptors based on the form of enzymatic activity of their intracellular domain upon activation:
Receptor tyrosine kinases (RTK) are receptor kinases that phosphorylate (add phosphate groups) to tyrosine residues on intracellular signaling proteins. There are seven subtypes of RTK with varying extracellular domains.
Receptor serine-threonine kinases are receptor kinases that phosphorylate serine and/or threonine residues on associated latent gene regulatory proteins.
Receptor guanylyl cyclases generate second messenger cyclic guanosine monophosphate (cGMP) from guanosine triphosphate (GTP) in the cytosol.
Histidine-kinase-associated receptors initiate a "two-component" signaling pathway in which the kinase phosphorylates itself on histidine and then passes the phosphate to a second intracellular signaling protein.
Another type is the receptor-like tyrosine phosphatases that remove phosphate groups from tyrosine in specific intracellular signaling proteins. They are considered “receptor-like” because their corresponding ligands have not yet been identified, meaning their function as receptors has not been explicitly demonstrated.
Mechanism for activation of enzyme-linked receptors
For most enzyme-linked receptors, ligand binding induces their dimerization or, in some cases, oligomerization. This causes cytoplasmic enzymatic domains to combine, resulting in a change in enzymatic activity, which is essentially their activation.
Dimerization can occur between separate receptors that bind the same ligand (heterodimerization) or between receptor chains of the same type (homodimerization).
RTKs, RTPs, and guanylyl cyclase receptors often form homodimers (the epidermal growth factor (EGF) receptor tyrosine kinase being an exception), whereas receptor serine–threonine kinases typically form heterodimers. While this is generally the case, there are times when activation requires the oligomerization of several receptors.
How enzyme-linked receptors activate signaling pathways
Now that we have discussed the definition and types of enzyme-linked receptors, here we will discuss specific examples--receptor tyrosine kinase and insulin--and how they activate signaling pathways.
Receptor Tyrosine Kinase
There are more than 16 structural subfamilies of receptor tyrosine kinases, each with its own family of protein ligands.
Extracellular signal proteins that operate via receptor tyrosine kinases include a wide range of secreted growth factors and hormones including insulin (which we will discuss further later).
When a ligand binds to the ligand-binding domain on the cell's surface, it activates the intracellular tyrosine kinase domain. Upon activation, the kinase domain moves a phosphate group from ATP to specific tyrosine side chains on receptor proteins as well as intracellular signaling proteins that interact with the phosphorylated receptors.
The rearrangement in receptor tyrosine kinases allows adjacent kinase domains of the receptor chains to cross-phosphorylate each other on numerous tyrosines, a process known as autophosphorylation.
Autophosphorylation of receptor tyrosine kinase cytosolic tails results in activation in two ways:
The phosphorylation of tyrosines inside the kinase domain boosts the enzyme's kinase activity.
The phosphorylation of tyrosines outside the kinase domain generates high-affinity docking sites in the target cell for the binding of various intracellular signaling proteins.
Once attached to the active kinase, the signaling protein may get phosphorylated on tyrosines and therefore activated. On the other hand, it could also be the case that binding alone suffices to activate the docked signaling protein.
Autophosphorylation acts as a switch to activate the transitory formation of a large intracellular signaling complex, which subsequently transmits signals to many parts of the cell. Different receptor tyrosine kinases bind different combinations of these signaling proteins, which in turn triggers varying reactions.
The binding of intracellular signaling proteins to a tyrosine kinase receptor that has been activated creates a signaling complex that can subsequently send signals along various signaling pathways. Some docked proteins are enzymes that activate the inositol phospholipid signaling pathway by which receptor tyrosine kinases can enhance cytosolic Ca2+ levels. Typically such receptors rely on relay chains of protein-protein interactions.
Enzyme-linked receptors insulin
Insulin is a hormone secreted by pancreatic b cells that acts through a receptor located in the membrane of target cells, the most important of which are:
The liver: where it promotes glucose storage into glycogen and decreases glucose output
Skeletal muscle and fat: where it stimulates glucose transport through GLUT4 translocation
B cells, brain cells, and many other types of cells: where it produces numerous and varying impacts
The insulin receptor is a member of the tyrosine kinase receptor superfamily. We have discussed the mechanism by which RTK activates signaling pathways, but insulin receptors are a bit different.
The insulin receptors are tetramers (composed of four identical building blocks) to begin with, and its interaction with a ligand is thought to result in the rearrangement of transmembrane receptor chains such that the two kinase domains are brought together. The majority of the phosphotyrosine docking sites formed by ligand interaction are found on a specific docking protein termed insulin receptor substrate-1 (IRS-1) rather than on the receptor itself.
The active receptor autophosphorylates its kinase domains, which subsequently phosphorylate IRS-1 on many tyrosines, resulting in more docking sites than the receptor alone could accommodate. Some receptor tyrosine kinases employ other docking proteins in a similar manner to increase the size of the signaling complex.
Enzyme-Linked Receptors - Key takeaways
- Enzyme-linked receptors are a type of cell-surface receptors that, once bound to a ligand, send a signal through the membrane and activating the enzyme, which triggers a series of reactions, eventually leading to a response.
- The extracellular domain of enzyme-linked receptors contains the signal's binding site, whereas the intracellular domain triggers the signal transduction pathway upon binding.
- There are four types of enzyme-linked receptors based on the form of enzymatic activity of their intracellular domain upon activation: receptor tyrosine kinases, receptor serine-threonine kinases, receptor guanylyl cyclases, and histidine-kinase-associated receptors.
- For most enzyme-linked receptors, ligand binding induces their dimerization or, in some cases, oligomerization.
- This causes cytoplasmic enzymatic domains to combine, resulting in a change in enzymatic activity, which is essentially their activation.
References
- Zedalis, Julianne, et al. Advanced Placement Biology for AP Courses Textbook. Texas Education Agency.
- Meyts, Pierre De. “The Insulin Receptor and Its Signal Transduction Network - Endotext - NCBI Bookshelf.” The Insulin Receptor and Its Signal Transduction Network - Endotext - NCBI Bookshelf.
- “Cell Signalling.” Cell Signalling, www.open.edu. Accessed 4 July 2022.
- Alberts, Bruce, et al. “Signaling through Enzyme-Linked Cell-Surface Receptors - Molecular Biology of the Cell - NCBI Bookshelf.” Signaling through Enzyme-Linked Cell-Surface Receptors - Molecular Biology of the Cell - NCBI Bookshelf, www.ncbi.nlm.nih.gov, 1 Jan. 2002.
- Purves, Dale, et al. “Receptor Types - Neuroscience - NCBI Bookshelf.” Receptor Types - Neuroscience - NCBI Bookshelf, www.ncbi.nlm.nih.gov, 1 Jan. 2001.
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Frequently Asked Questions about Enzyme-Linked Receptors
What are enzyme-linked receptor?
Enzyme-linked receptors are a type of cell-surface receptors that, once bound to a ligand, send a signal through the membrane and activating the enzyme, which triggers a series of reactions, eventually leading to a response.
Which are 4 types of enzyme-linked receptors?
There are four types of enzyme-linked receptors based on the form of enzymatic activity of their intracellular domain upon activation: receptor tyrosine kinases, receptor serine-threonine kinases, receptor guanylyl cyclases, and histidine-kinase-associated receptors.
Do Enzyme-linked receptors activate G proteins?
Enzyme-linked receptors in the plasma membrane interact with activated G proteins.
How are G linked and tyrosine kinase receptors the same?
Like G protein coupled receptors, the extracellular domain of enzyme-linked receptors contains the signal's binding site, whereas the intracellular domain triggers the signal transduction pathway upon binding.
how are enzyme linked receptors activated?
For most enzyme-linked receptors, ligand binding induces their dimerization or, in some cases, oligomerization. This causes cytoplasmic enzymatic domains to combine, resulting in a change in enzymatic activity, which is essentially their activation.
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