Monday, February 25, 2013

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.