Insulin Receptor - Online Tutor, Practice Problems & Exam Prep

Insulin signaling initiates with ligand binding, where insulin binds to the insulin receptor (INSR), a receptor tyrosine kinase (RTK) with two alpha and two beta subunits linked by disulfide bonds. This binding leads to autophosphorylation of the beta subunits, activating the receptor. The insulin receptor substrates (IRS), particularly IRS 1, act as adapter proteins, facilitating signal transduction by bridging other proteins. IRS 1 activation creates branching pathways, influencing various cellular responses, such as glucose metabolism and cell growth, highlighting the complexity of insulin's biological effects.

Insulin Receptor

Alright. So here we're going to briefly revisit our map of the lesson on biosignalling pathways, which is down below right here. And of course, we know that we've been exploring this map by following the leftmost branches first. And already at this point in our course, we've covered the GPCRs, proteins, the G protein-coupled receptors, and we've talked about all of these pathways that you see down below in our previous lesson videos. So currently, we've been exploring the new branch over here for receptor tyrosine kinases. We're starting to talk about very specific receptor tyrosine kinases. We've introduced insulin, and here in this video, we're going to introduce the insulin receptor, so let's get started with that. So here we're going to introduce the insulin receptor as we introduce insulin biosignalling. Insulin signaling actually begins with just 2 steps that we have numbered down below, number 1 and number 2. And of course, the number 1 and number 2 in our text corresponds with the number 1 and the number 2 down below in our image.

In the very first step of insulin signaling, what we have is ligand binding, which is pretty much exactly what it sounds like. The ligand is going to bind to its receptor. Now we know that in insulin signaling, the ligand is going to be insulin itself, and we know that insulin can elicit a wide variety of biological effects. However, what's really important to note is that insulin actually does not enter cells. Instead, insulin is going to elicit all of its biological effects through biosignalling and signal transduction. Instead of entering cells, insulin is actually going to bind to an insulin receptor in the plasma membrane. The insulin receptor, as you can see by these bolded letters right here, is commonly abbreviated as just INSR. The insulin receptor or INSR is really just a specific type of RTK or receptor tyrosine kinase, and it's going to be activated of course by insulin binding here, which is why this step is called ligand binding. Insulin is again going to be the ligand here in this scenario.

Now the insulin receptor, as we'll see down below in our image, actually has 4 protein subunits. It has 2 alpha subunits and 2 beta subunits that are linked together via disulfide bonds. You might recall that disulfide bonds are covalent bonds between the Rgroups of 2 cysteine residues. The insulin receptor is actually a little bit unusual because it's not like the other typical RTKs that exist as individual separate monomers prior to ligand binding. The reason the insulin receptor is so unusual is that even in the unliganded state, even when it's not bound to its ligand insulin, the insulin receptor still already exists as 2 alpha-beta dimers. Because it already exists as 2 alpha-beta dimers, really no dimerization step is required.

If we take a look at our image down below, over here on the left hand side, notice at the top here, what we have is the Insulin Peptide. Insulin is going to act as the ligand here in this scenario. Notice below this, what we have is the insulin receptor that is going to be embedded in the plasma membrane. Notice that this insulin receptor has 4 protein subunits. It has 2 alpha subunits that you see here and 2 transmembrane beta subunits. By the positioning here, you can see that the 2 alpha subunits in green are involved with ligand binding or binding to the insulin molecule. The 2 beta subunits are transmembrane and they contain the cytoplasmic tyrosine kinase domains. The insulin receptor is an RTK, a receptor tyrosine kinase. Another thing to note is that these subunits on the insulin receptor are actually all disulfide-linked together, and you can see those disulfide links here.

What this means is that these guys are covalently linked together and they already exist, as we indicated above, as 2 alpha-beta dimers. Here's one alpha-beta dimer and here's the other alpha-beta dimer. It already exists as a dimer so we can pretty much skip the dimerization step. Since we can skip the dimerization step, what that means is in step number 2, what we have is the insulin receptor autophosphorylation, which recall that autophosphorylation is self-phosphorylation or cross-phosphorylation when 2 subunits phosphorylate each other. This is when the tyrosine kinase domains in the insulin receptor's beta subunits are going to cross-phosphorylate each other and thus activate each other.

Down below, notice in our step number 2, what we have is the autophosphorylation of the beta subunits of these ends of this insulin receptor. You can see here by these arrows that they are cross-phosphorylating each other at Tyrosine Residues. Recall that the 'Y's are the one-letter amino acid codes for Tyrosine. What we have is the Tyrosine Residues being phosphorylated and that is going to fully activate the Tyrosine Kinase Domains. The alpha and the beta domains are linked together via disulfide bonds. Again, you can see those disulfide bonds throughout our images right here. That means we can skip the dimerization step because it is already dimerized. That's why we have step number 1, ligand binding, and step number 2, autophosphorylation. Really, this is the first two steps of insulin signaling. We've introduced our insulin receptor. That concludes this video, and I'll see you guys in our next one.

Insulin Receptor Example 1

Alright. So here we have an example problem that wants us to complete the sentence using one of these five potential answer options down below. It says, for the insulin receptor to transduce the signal inside the cell, and option a says, the G α subunit needs to bind GTP to activate adenylate cyclase. Now of course, what we need to recall from our previous lesson videos is that the insulin receptor is an RTK or a receptor Tyrosine Kinase, and receptor Tyrosine Kinases are different receptor proteins than GPCRs, G protein-coupled receptors. And so recall that G α subunit is the subunit of a G protein, and G proteins are part of GPCR pathways, and they are not part of RTK pathways. And so what this means is that any of these answer options such as option a and b that include G α subunit is going to be incorrect because it's referring to the wrong type of pathway. Now, also, if we take a look at option d, it says that it needs to recruit a Tyrosine Kinase. And so by recruitment, what that means is it needs to essentially bring in a separate Tyrosine Kinase, but that is not what RTKs need to do. RTKs already have a covalently bound Tyrosine Kinase domain, and so, really, they don't need to recruit Tyrosine Kinases, for the most part. However, later in our course, we will talk about an exception to this. But here, the insulin receptor that we discussed in our last lesson video does not need to recruit a Tyrosine Kinase. It also mentions after dimerization, but again, we know that the insulin receptor is a unique RTK in the fact that it is actually already dimerized. And so there's really no dimerization step that is required since it forms these covalent disulfide bonds between its alpha beta subunits. We can eliminate option d for those reasons. And option e says it needs to recruit a Tyrosine Phosphatase to phosphorylate the cytoplasmic domain after dimerization. And so again, it's mentioning recruitment, so we know that it doesn't need to recruit that, but it also says Tyrosine Phosphatase. Recall, phosphatases do not phosphorylate things; instead, they do the opposite. They remove phosphate groups. And so for that reason, we know for sure this does not match up with the insulin receptor. And so, of course, this only leaves answer option c as the correct answer, and so for the insulin receptor to transduce the signal inside the cell, it needs to activate its Tyrosine Kinase domains via autophosphorylation after binding the insulin ligand. And so c here is the correct answer to this practice, and that concludes this practice or this example, and I'll see you guys in our next video.

The insulin receptor is an example of a _______:

• A. G-protein coupled receptor.
• B. Receptor tyrosine kinase.
• C. Receptor tyrosine phosphatase.
• D. Membrane channel protein.
• E. Receptor threonine kinase.

Insulin Receptor

So in this video, we're going to introduce the insulin receptor substrates or IRS for short. And so, again, the insulin receptor substrates, as you can see by these bolded letters here, are commonly referred to as just IRS, insulin receptor substrates. And as their name implies, these are literally the substrates of the fully active insulin receptor. And so more specifically, the insulin receptor substrates are actually really small proteins or peptides that again are going to be the main targets and the main substrates of fully active autophosphorylated insulin receptor or INSR. Now, really, there are many different types of insulin receptor substrates or IRS that are distinguished from each other by numbers. And so IRS 1 is just one specific type of insulin receptor substrate. But really moving forward in our course, IRS 1 is going to be the main insulin receptor substrate that we're going to focus on in this clutch prep biochemistry course. And so again, IRS 1 is an insulin receptor substrate, and more specifically, IRS 1 is a secondary messenger that helps to transmit the insulin receptor signal as what's known as an adapter protein. But what in the world are these adapter proteins? Well, adapter proteins are defined as proteins that lack enzymatic activity, so they don't actually catalyze any reaction. Instead, they serve mainly as a bridge to help bring other proteins together and to help continue the signal transduction pathway. And so if we take a look at our image down below, notice over here on the left hand side, what we have is our ligand bound, our insulin, bound insulin receptor here that is fully autophosphorylated and fully active. And so, of course, the fully active autophosphorylated insulin receptor that we have highlighted here, is going to have fully active Tyrosine Kinase domains that are capable of phosphorylating its targets or its substrates. And so here we're showing you the insulin receptor substrate 1 or IRS 1. And notice on the left here, it is not phosphorylated, but after the activity of the fully activated autophosphorylated insulin receptor, notice that IRS 1 becomes phosphorylated at these positions here and that activates IRS 1. And so, because again these are Tyrosine Kinase domains, that means that IRS 1 is going to be phosphorylated at tyrosine residues. Now depending on the cell type and the conditions within the cell, IRS 1 can actually induce various other signaling pathways. And so what we'll see moving forward in our course is that insulin's RTK signaling pathway is usually always going to result in IRS one activation, as you can see down below, the activated or phosphorylated IRS 1. But then after IRS 1 is activated, this actually is going to branch at this point. And so after, again, IRS 1 activation, it then branches at this point. And so this is a very important thing for you guys to take note of. And so what this means is that IRS 1 is going to act as a branch point in the Insulin RTK signaling pathway. And so notice down below in our image, right here, as soon as insulin binds and causes the autophosphorylation of the insulin receptor, the insulin receptor phosphorylates and activates IRS 1. Again, IRS one is going to act as a branch point which is why we see that the signal transduction pathway splits, as soon as IRS 1 is activated. And so what you'll notice is that IRS 1 is going to act as an adapter protein. Again, meaning that it does not have enzymatic activity, but it is going to bring other proteins together. And so, of course, it's the SH2 domains of these proteins that will bind to the phosphorylated tyrosine residues. And so notice that it's capable of bringing together different proteins, and that again is part of what leads to this branch point. And so, again, depending on the cell type and the conditions and the proteins that it brings together, this pathway could lead to a different cell response. So notice protein 1 here is leading to cell response number 1, which would be, for example, changing glucose metabolism. But notice that bringing protein number 2, together with IRS 1 would actually create a different cell response, cell response number 2, which could be, for instance, cell growth, and regulation of gene expression, and things like that. And so, this is why we've seen that insulin can actually create several different biological effects, partially because again IRS one acts as this branch point. Now moving forward in our biochemistry course here at Clutch Prep, we're going to talk specifically about the insulin RTK signaling pathways that lead to cell response number 1, changes in glucose metabolism, as well as the biosignaling pathways that lead to cell response number 2, cell growth. And so first, we're going to start off with, cell response number 1, glucose metabolism. So, stay tuned as we move forward in our course and continue to talk more and more about insulin and the insulin signaling. So, that concludes this video on the insulin receptor substrates or IRS, and I'll see you guys in our next video.

Insulin binds to a receptor that:

I. Is coupled to a G protein.
II. Possesses tyrosine kinase activity.
III. Possesses serine/threonine phosphatase activity.
IV. Interacts with the adapter protein IRS-1.

• A. I, III and V.
• B. II and IV.
• C. I, II and V.
• D. II, IV and V.
• E. IV and V.

Which of the following is TRUE concerning the interaction between the insulin receptor and IRS-1:

• A. The IRS protein phosphorylates the insulin receptor.
• B. The β-subunits of the receptor bind to insulin, where each subunit has a separate insulin binding site.
• C. Each β-subunit acts as a serine kinase and auto-phosphorylates the other subunit.
• D. IRS is phosphorylated by the tyrosine kinase domains in the β-subunits of the insulin receptor.
• E. IRS contains phosphorylated threonine residues that directly bind to insulin.

Here’s what students ask on this topic:

What is the structure of the insulin receptor?

The insulin receptor (INSR) is a receptor tyrosine kinase (RTK) composed of four protein subunits: two alpha (α) subunits and two beta (β) subunits. These subunits are linked together by disulfide bonds, which are covalent bonds between the R groups of two cysteine residues. The α subunits are involved in ligand binding, specifically binding to insulin, while the β subunits are transmembrane and contain the cytoplasmic tyrosine kinase domains. This structure is unique because the insulin receptor exists as two αβ dimers even in the unliganded state, meaning no dimerization step is required upon insulin binding.

How does insulin binding activate the insulin receptor?

Insulin binding to the insulin receptor (INSR) initiates the activation process. When insulin, the ligand, binds to the α subunits of the receptor, it triggers autophosphorylation of the β subunits. Autophosphorylation involves the tyrosine kinase domains in the β subunits cross-phosphorylating each other at tyrosine residues. This phosphorylation fully activates the tyrosine kinase domains, enabling the receptor to phosphorylate downstream targets, such as insulin receptor substrates (IRS), and propagate the insulin signaling pathway.

What role do insulin receptor substrates (IRS) play in insulin signaling?

Insulin receptor substrates (IRS), particularly IRS 1, play a crucial role in insulin signaling as adapter proteins. Once the insulin receptor (INSR) is fully activated through autophosphorylation, it phosphorylates IRS proteins at tyrosine residues. IRS 1, the primary focus in many studies, acts as a bridge to bring other proteins together, facilitating the continuation of the signal transduction pathway. This branching point allows IRS 1 to influence various cellular responses, such as changes in glucose metabolism and cell growth, depending on the cell type and conditions.

What are the main steps in the insulin signaling pathway?

The insulin signaling pathway begins with two main steps: ligand binding and autophosphorylation. In the first step, insulin binds to the insulin receptor (INSR), which consists of two α and two β subunits linked by disulfide bonds. This binding activates the receptor, leading to the second step, autophosphorylation. During autophosphorylation, the tyrosine kinase domains in the β subunits cross-phosphorylate each other at tyrosine residues, fully activating the receptor. This activation allows the receptor to phosphorylate downstream targets, such as insulin receptor substrates (IRS), which further propagate the signaling pathway.

How does IRS 1 function as an adapter protein in insulin signaling?

IRS 1 functions as an adapter protein in insulin signaling by acting as a bridge to bring other proteins together, facilitating signal transduction. Once the insulin receptor (INSR) is fully activated and autophosphorylated, it phosphorylates IRS 1 at tyrosine residues. As an adapter protein, IRS 1 lacks enzymatic activity but plays a crucial role in continuing the signaling pathway. It creates a branching point, allowing the signal to diverge into different pathways, leading to various cellular responses such as changes in glucose metabolism or cell growth, depending on the specific proteins it brings together.