Sunday, February 24, 2013

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