Types of Receptors - Part 4

As we have seen in the previous post that the majority of the receptors are enzyme linked that stimulate the protein-tyrosine phosphorylation. Here, in this last post regarding the types of receptors, we will discuss about the other types of receptors that are associated with some other enzymatic activities. These are: protein tyrosine phosphatases, protein serine/threonine kinases and guanylyl cyclases. Lets understand briefly about each of these classes one by one below.

Protein Tyrosine Phosphatases:

Here, the name suggests the function i.e; phosphatases which is to remove phosphate group from phosphotyrosine residues. Thus, these receptors play a role opposite to that of protein tyrosine kinases thereby counterbalancing the kinases (just to recall, the kinases, add phosphate groups to the tyrosine residues). In some cases, the protein tyrosine phosphatases play a negative role in cell signaling pathways by stopping the signals which were initiated by protein-tyrosine phosphorylation. Whereas in some cases, the protein tyrosine phosphatases play a positive role in cell signaling by their enzymatic activities.

Serine/Threonine Kinases:

The receptors for some polypeptides phosphorylates serine or threonine residues instead of tyrosine residues on their substrate molecules. An example of such receptor is Transforming Growth Factor-β (abbreviated as TGF-β) which falls under this class of receptors i.e.; serine/threonine receptors. TGF-β is a family of growth factors which is involved in the control of proliferation and differentiation of various cell types. When the ligand binds, there is an association of two different types of polypeptides (both of which are encoded by different TGF-β receptor family) and hence forms the heterodimers. Here, one of the receptor kinases phosphorylates another one. This activated TGF-β receptors then phosphorylates another group of transcription factors called Smads, which then translocates to nucleus and causes the expression of targeted genes. The entire TGF-β signaling will be explained in the further post.

Guanylyl Cyclases:

Another class of receptors is guanylyl cyclases. Guanylyl cyclases have the cytosolic domain which catalyzes the formation of cyclic GMP. As we have seen earlier, that the signaling molecule, nitric oxide, also stimulates the guanylyl cyclase. However, the target of NO is intracellular enzyme as against the transmembrane receptor.
The receptor guanylyl cyclases have extracellular domain that binds the ligand, a single transmembrane α-helix and a cytosolic domain which has the catalytic activity. Thus, when the ligand binds at the extracellular domain, cyclase activity is stimulated which results in the formation of cyclic GMP - a second messenger.

So, finally, her we finish almost all the classes of receptors. Now, from the next post, we will proceed to the pathways of intracellular signal transduction.

Types of Receptors - Part 3

In this post, I will discuss about the next class of receptor - Cytokine Receptors and Nonreceptor Protein Tyrosine Kinases.
The basic principle behind the functioning of these receptors is that they stimulate the intracellular protein-tyrosine kinases. The receptors are associated with these kinases by non-covalent bonds. This is unlike protein-tyrosine kinases (discussed here) where there is intrinsic enzymatic activity. Lets understand these receptors in detail.
First of all, what all types of receptors are included in this family? So, the answer is the receptors for most cytokines (for example, interleukin-2, erythropoietin) as well as some of the peptide hormones (like, growth hormones) are included in this superfamily of cytokine receptors. Lets understand the structure and functioning of these receptors.

Structure:

The structure is similar to that of protein tyrosine kinase receptors. So, the cytokine receptors have an N-terminal, C terminal and a transmembrane. The N-terminal is the extracellular domain that binds to the ligand while the C-terminal is cytosolic domain. The transmembrane is single and is alpha helical. Now, you might be thinking, if the structure of cytokine receptors is exactly the same as that of protein tyrosine kinase receptors (described in earlier post), then why cytokine receptors are placed in a different class. OK, I will now make it clear that there is one main difference between the two types of receptors - in the cytokine receptors, there is no catalytic activity in the C terminal (cytosolic domain) as against protein-tyrosine kinase receptors which possesses tyrosine kinase activity in C-terminal. So, next question you might be wondering is how do then, cytokine receptors function? The answer is that these receptors function in association with nonreceptor protein-tyrosine kinases, which are activated when ligand binds at the N-terminal. The description below regarding the functioning of these receptors will make your concept all the more clear.

Functioning:

Receptor Dimerization: The binding of the ligand at the N-terminal induces the receptors to dimerize.
This dimerization leads to cross-phosphorylation of the associated nonreceptor tyrosine kinases (as can be seen in the third figure in the adjacent diagram explaining the functioning).
These activated non-tyrosine kinases then phosphorylates the cytokine receptor (last figure in the adjacent diagram) and thus, provide phosphotyrosine binding sites. These binding sites then recruit the downstream signaling molecules and these molecules contain SH2 domains.

So, here, if we want to compare the two receptors (cytokine receptors and protein tyrosine kinase receptors) then, we can think of the analogy that the combination of cytokine receptors plus the nonreceptor protein-tyrosine kinases functions similar to that of protein tyrosine kinases.
One of the kinases which are associated with cytokine receptors and nonreceptor protein tyrosine kinases belong to the family of Janus Kinases (JAK) which consists of four closely related nonreceptor tyrosine kinases.
Another nonreceptor protein kinases belong to the family of Src, which consists of Src and eight closely related proteins.

Types of Receptors - Part 2

In this post, I will discuss about the next cell-surface receptor which is Protein-Tyrosine Kinases. These types of cell-surface receptors are directly linked to intracellular enzymes i.e.; this is enzyme-linked receptor. The protein tyrosine kinases is the largest family of such types of receptors.

Why are receptors called so? For that, first, you must know the function of kinases?  Kinases transfer high energy phosphate groups from one molecule to another. Now, the phosphate groups from the receptor is transferred to tyrosine residues on substrate molecule. In other words, these receptors phosphorylate on tyrosine residues on the substrate proteins; and hence the name Protein-Tyrosine kinases.I hope this is clear to you.

There are a wide variety of receptors that fall under this category, like receptors for EGF (Epidermal Growth Factor), NGF (Nerve Growth Factor), PDGF (Platelet-Derived Growth Factor), insulin and many such other growth factors. All these receptors share a common structure which is described below.

Structure: 

All the receptors under protein-tyrosine kinases have a common structural organization. All these receptors possess two terminals as N-terminal and C-terminal and a transmembrane protein. The  N-terminal is the extracellular ligand-binding domain while the C-terminal is the cytosolic domain with protein-tyrosine kinase activity. The middle portion is a single transmembrane alpha helix. Although maximum number of receptors consists of single polypeptide chain, however, some receptors do have two polypeptide chains (dimers) like insulin receptor.

Functioning:
Lets make the functioning easy to remember and recall by dividing into different steps as:

Receptor Dimerization: The first step in the signaling by these protein-tyrosine kinase receptors is the dimerization of receptors. When there is binding of ligand at the N-terminus of the receptor, then the receptors dimerize. Thus, we can say that the dimerization is induced by ligands (like growth factors). The receptors of some growth factors (like EGF) are monomers and they undergo dimerization so as to result in conformational change. These conformational changes helps in protein-protein interaction between different receptor polypeptide chains. However, there are receptors of some growth factors like NGF and PDGF which are dimers and consists of two identical polypeptide chains. Here, the growth factors directly dimerize by binding to two different receptor molecules simultaneously.
Autophosphorylation: The next step after ligand-induced dimerization is autophosphorylation. The dimerized polypeptide chains cross phosphorylate one another (as can be seen in the diagram). This leads to following events:
a. As there is phosphorylation of these tyrosine residues, it increases the protein kinase activity in the catalytic domain.
b. Secondly, phosphorylation of the tyrosine residues creates specific binding sites for additional proteins outside the catalytic domain which further transmits the intracellular signals to the downstream molecules.

These downstream signaling molecules associates with the receptor (protein-tyrosine kinase) with the help of various protein domains present within the downstream signaling molecules. These protein domains are specific to phosohotyrosine containing peptides. Hence, we can say, there is association of downstream signaling molecules with the receptor; mediated by specific protein domains.

An example of one such domain which was one of the first to be characterized is SH2 domain. Why the name SH2? It stands for Src Homology 2 (where Src is an oncogenic protein) as it was initially recognized in protein-tyrosine kinases related to Src.  These SH2 domains bind to specific sequences which contains phosphotyrosine resides.
Another example of such domain is PTB domain where PTB stands for Phospho-Tyrosine Binding. There are some other proteins (which do not bind via SH2 domains) that bind via PTB domains.
The effects of protein binding to activated protein-tyrosine kinase receptor via SH2 domain or PTB domain are as follows:
a. The protein gets localized to plasma membrane
b. There is association of several other proteins with protein/s
c. Promotes the phosphorylation of several other proteins
d. Ultimately stimulates their enzymatic activity

Types of Receptors - Part 1

Before understanding the pathways and mechanisms of complicated cell-cell signaling, lets make it easy by first understanding the different types of cell receptors and how do they function. Understanding this, will make the cell-cell signaling very clear and easy to remember.

From our previous posts, we can recall that cell-cell signaling requires binding of the signaling molecules to the cell-surface receptors on the target cells. So, lets first understand different classes of cell surface receptors with their functioning. In the next few articles, we will be learning about classes of cell surface receptor then followed by the pathways and the mechanisms of signaling and communication (downstream signaling).

Lets start our discussion with the first family of cell receptors which is also the largest - G-Protein Coupled Receptors, abbreviated as GPCRs. You might be thinking what is this "G-protein"? The G-protein stands for guanine nucleotide binding protein. The G-protein coupled receptors or GPCRs utilizes these G-proteins as an intermediate to transmit signals to intracellular targets. There are around thousands of GPCRs. Do you know, that these receptors are also responsible for our various senses like smell, sight and taste? Isn't it interesting to know how it works? Before that, lets understand the structure of GPCRs.

Structure:
The G-protein coupled receptors consists of proteins which are characterized by seven α-helices (as can be seen in the adjacent figure) that span the membrane and hence are called membrane-spanning α-helices.

G proteins consists of three subunits as α, β and γ. They are also referred to as heterotrimeric G proteins. What is the role of these subunits, we will see in the functioning of the receptor. Before understanding the functioning, just remember:
α-subunit bound to GDP ---- Inactive State

α-subunit bound to GTP ---- Active State

Functioning: 
The α-subunit binds to guanine nucleotide which regulates G-protein activity. In the resting stage, the α-subunit is bound to GDP in association with β and γ subunits (here, α-subunit bound to GDP is inactive state) (in the adjacent figure - the topmost diagram). When the hormone binds to the extracellular domain of these receptors, there is a change in the conformation of the receptors such that the cytosolic domain of the receptor interacts with the G-protein. This leads to the release of GDP from α-subunit and in turn it gets exchanged with GTP. This α-subunit which is now bound to GTP (active state), dissociates with β and γ subunits and these two subunits remain together as βγ complex (the left diagram in the above figure).
The α-bound GTP and βγ complex functions by interacting with their respective targets and gives an intracellular response. When there is hydrolysis of GTP, the activity of  α-subunit is terminated and this inactive α-subunit (which is bound to GDP) then re-associates with βγ complex and the cycle starts again.

There is a wide range of α, β and γ subunits. For example, mammalian genome codes for around 20α subunits, 5β subunits and 12γ subunits. Different G proteins associate with different receptors and hence, there are distinct intracellular targets.

(Note: What makes it binds to GTP after conformational change. GDP (guanine dinucleotide phosphate has two phosphate groups while, guanine trinucleotide phosphate, GTP has three phosphate groups. So, when there is an active state (conformational change), the conformation is such that it can accommodate 3 phosphate groups and hence GDP is replaced by GTP.