Enzyme-linked receptor proteins either possess an in-built enzyme or associate with separate enzymes in the cytoplasm. These enzymes are activated upon ligand binding. They relay the extracellular signal to the nucleus by a sequence of interactions that eventually turn on specific transcription factors, altering gene expression in the cell.
All enzyme-linked receptors share a few common features;
1. Ligand-binding domain
2. Transmembrane domain
3. Cytosolic "active" enzyme domain
Within an organism, the processes of metabolism, growth, and differentiation must be tightly integrated for correct function. Cell signalling essentially connects and lubricates these occurances to ensure that progress runs smoothly.
Doesn't it seems quite handy therefore, that "lubricating" is an easy way to remember the mechanism of signal relay by enzyme linked receptors...?!
Ligands are released into the extracellular space
to their Receptor
specific Interactions cause a
Conformational change within the catalytic domain,
this Activates the connected enzyme,
phosphorylation generates Tethering sites
where Intracellular effector proteins bind
these further relay the signal to the Nucleus
resulting in changes in Gene expression
There are three main types of enzyme-linked receptors:
1. Receptor serine-threonine kinases e.g. transforming growth factor-beta (TGFB) receptors.
2. Receptor tyrosine kinases (RTKs) e.g. growth factor receptors.
3. Tyrosine-kinase-associated receptors e.g. cytokine receptors.
The figure below compares each aspect of the three signalling pathways which are explained in more detail in the following sections.
There are two types of serine/threonine kinase receptors, both of which contain an intracellular kinase domain. They are each dimeric proteins, so an active receptor complex is made up of four receptors.
1. Type I receptors
2. Type II receptors
Type I receptors are kept inactive by a portion of its cytosolic domain that blocks its kinase activity.
TGFB/bone morphogenetic protein (BMP)/activin ligands bind as dimers to Type II receptors.
Type II receptors then bind to, and phosphorylate, Type I receptors. This removes the inhibition of Type I kinase activity.
Type I receptors then phosphorylate Smad transcription factors, allowing them to dimerise and enter the nucleus to repress or activate target gene expression.
For an animation of this pathway see: http://www.youtube.com/watch?v=QoJBIfM0bmU
RTK ligands, such as fibroblast growth factor (FGF), epidermal growth factor (EGF), nerve growth factor (NGF) etc. bind as dimers.
1. Ligand binding to RTK monomers results in dimer formation.
2. Receptors possess an intracellular tyrosine kinase domain. Within the dimer the conformation is changed, locking the kinase into an active state.
3. The kinase of one receptor then phosphorylates a tyrosine residue contained in the "activation lip" of the second receptor.
This forces the activation lip out of the kinase active site, allowing ATP bind and resulting in enhanced kinase activity.
This induces phosphorylation at further tyrosine residues.
4. Phosphotyrosine is a conserved "docking site" for many intracellular signal transduction proteins that contain SH2 domains (see further down the page for more information).
For animations and summaries of this pathway see:
Cytokines are the main ligands that signal through tyrosine kinase-associated receptors.
Like RTKs and RS/TKs these receptors activate a cascade of phosphorylation BUT they do not possess a tyrosine kinase domain.
The intracellular side of each receptor is bound to a cytosolic tyrosine kinase protein.
1. Cytokines bind simultaneously to two receptor monomers.
2. This brings the two associated kinases closer together.
3. One kinase phosphorylates the other kinase in an area called the "activation lip" (similar to RTK activation).
The activation lip moves out of the active site and binds ATP therefore enhancing kinase activity.
4. The enhanced kinase phosphorylates more tyrosine residues on the intracellular portion of the receptor.
5. Phosphotyrosines serve as "docking sites" for SH2 domain-containing proteins (see section further down the page for more information)
For an animation of the tyrosine-kinase-associated receptor pathway janus kinase (JAK)-signal transducer and activator of transcription (STAT) see:
Src homology 2 (SH2) domains bind to phosphotyrosine residues, along with other similar domains such as the phosphotyrosine-binding (PTB) domain.
These domains are found in a HUGE variety of proteins....
- enzymes such as kinases, phosphatases
- scaffolding proteins that promote the formation of protein complexes
- adaptors that act alongside receptors to promote function
- regulators that inhibit or dampen signalling by the receptor
...all of which play a role in regulating "cross-talk" between different signalling pathways.
It's important to note that SH2 domain-containing proteins are very specific; they do not simply bind to any old phosphotyrosine residue, but take into account other amino acid residues around this site.
Alberts, B et al (2008) "Signaling through enzyme linked receptors" in Molecular Biology of the Cell, 5th Edition. New York, Garland Science
Lodish, H et al (2008) "Cell Signaling I and II" in Molecular Cell Biology, 6th Edition. New York, W. H. Freeman and Company
Fastbleep © 2019.