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Insulin Receptor
Introduction
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Every jmol window should have a caption so we know what we are looking at (include the name of the molecule and pdb code) Replace "insert caption here' with 'your caption'. This didn't work for me when the jmol window was not part of this section. Since you can have captions in every section, you can all make cool scenes & captions for consideration for the Molecular Playground.
The insulin receptor is a tyrosine kinase, that is a type of ligand-activated receptor kinase. The crystallized protein, shown here, is the of the insulin receptor, as it is difficult to crystallize the protein and determine the structure when the greasy transmembrane portion of the protein is included. Four FAB antibodies (shown in peach, yellow, light green, and light blue) are attached to the protein to aid in crystallization. The insulin receptor is to the membrane at the beta strand, which extends through the cell membrane. The receptor is attached to the cell membrane by the beta strand, which extends through the membrane and into the interior of the cell and mediates activity by the addition of phosphate to tyrosines on specific proteins in cell. Tell us what we are looking at: ectodomain only (why?) What are the other parts? Explain color schemes. Orient us: where is the membrane? Where does ligand bind? "The folded over.." sentence doesn't make sense to me -- maybe later.
Insulin receptors are found in many diverse organisms organisms, from cnidarians and insects to humans. In humans, correctly functioning insulin receptors are essential for maintaining glucose levels in the blood. The insulin receptor also has role in growth and development (through insulin growth factor II); studies have shown that signalling through IGF2 plays a role in the mediation embryonic growth. [1]
In everyday function, insulin binding leads to increase in the high-affinity glucose transporter (Glut4) molecules on the outer membrane of the cell in muscle and adipose tissue. Glut4 mediates the transport of glucose into the cell, so an increase in Glut4 leads to increased glucose uptake. Insulin has two different receptor-binding surfaces on opposite sides of the molecule, that interact with two different . The first binding insulin surface interacts with a site on the L1 module as well as a 120-amino-acid peptide from the insert in FnIII-2. The second binding site consists of resides on the C-terminal portion of L2 and in the FnIII-1 and FnIII-2 modules [2]. Binding sites are shown highlighted in both monomers of the biologically functional dimer. [3]
Maintaining appropriate blood glucose levels is essential for appropriate life-sustaining metabolic function, and insulin receptor malfunction is associated with several severe diseases. Insulin insensitivity, or decreased insulin receptor signalling, leads to diabetes mellitus type 2. Type 2 diabetes is also known as non-insulin-dependent or adult onset diabetes, and is believed to be caused by a combination of obesity and genetic predisposition. In type 2 diabetes, cells are unable to uptake glucose due to decreased insulin receptor signaling, which leads to hyperglycemia (increased circulating glucose). Type 2 diabetes can be managed with dietary and lifestyle modifications to aid in proper metabolism.
Mutations in both copies of the insulin receptor gene causes Donohue syndrome, which is also known as leprechaunism. Donohue syndrome is an autosomal recessive disorder that results in a totally non-functional insulin receptor. The disorder results in distorted facial features, severe growth retardation, and often death within a year.[4] A less severe mutation of the same gene causes a much milder form of the disease in which there is some insulin resistance but normal growth and subcutaneous fat distribution.[5]
Overall Structure
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The ectodomain of the insulin receptor is a of 2 identical monomers. Each v-shaped is composed of 6 domains, three on each side of the V, shown in different colors. The red (L1) is involved in substrate binding. Its main feature is a 6 parallel stranded beta sheet. The orange (CR) is composed mostly of loops and turns. The yellow domain is a second , (L2) which contains a five parallel stranded beta sheet and several surface alpha helices. [6]
The next three domains are Fibronectin Type III domains. Fibronectin domains, characterized by beta sandwiches, are named after the protein fibronectin, which contains 16 of these domains.[7] The green FnIII-1 , contains one antiparallel and one mixed beta sheet. The blue FnIII-2 contains an insert domain of 120 residues. The purple FnIII-3 contains just four beta strands. Each domain occurs twice in the .[8]
The insert domain of the FnIII-2 domain separates the alpha and beta chains of each monomer. The alpha chain contains the L1, CR, L2, FnIII-1 domains and part of the FnIII-2 domain. The beta chain contains the rest of the FnIII-2 domain and the FnIII-3 domain. The insert domain starts and ends with a cleavage site where the chain is cut. The alpha and beta chains are then linked by a single between cysteines C647 and C860, leaving the insert domain as a separate peptide which forms disulphide bonds with cysteines in the FnIII-1 domain. The alpha chain lies completely on the exterior of the cell, while the end of the beta chain extends through the cell membrane and is involved in signaling.[9] This section of the beta chain, after the FnIII-3 domain in the sequence, is not shown in the structure which reflects only the . There are few interactions between the two legs of the monomer- just two salt bridges near the connection between the L2 and FnIII-1 domains. However there are many interactions between the two monomers including salt bridges and disulphide bonds.[10]
This structure is significant relative to previous structures for the protein because of the relative position of the L1 domains in the two monomers of the biological unit. In previously proposed structures, the L2, CR, and L1 domains formed a straight leg of the V similar to that of the fibronectin leg. With this model, it was thought that both L1 domains could bind to a single insulin molecule. With this folded over structure of the L2-CR-L1 leg, it is clear that this is not the case, as the L1 domains of each monomer face away from each other.[11]
Binding Interactions
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The insulin receptor's (IR) main substrate is insulin, which is referred to as insulin receptor substrate 1 (IRS-1). As insulin binds to the IR, the IR is phosphorylated. Phosphorylation of tyrosine residues in the IR leads to an increase in the glucose transporter (Glut-4) which has a high affinity for glucose molecules. This occurs mainly in muscle and adipose (fat) tissues where glucose uptake is most needed. This increase in Glut-4 causes an increase in glucose uptake from blood. Simply stated, 3loh is activated by insulin (IRS-1) which signals for an increase in Glut-4. Glut-4 finds its way to the cell surface where it can perform its function and transport glucose into the cell.
The binding mechanism and site are not completely understood. What is known, however, is that insulin is able to bind at two different locations on each monomer of the insulin receptor. Since there are two monomers in the biologically functional ectodomain, there are in total four locations available for binding and interaction. These locations are explained in the Introduction section of this page. Current literature describes the locations for insulin binding as follows: the region between L1 and Fn2 as site 1, the region involving L2, Fn1, and Fn2 as site 2. Based on knowledge of the structure of the insulin receptor (it is a dimer with anti-mirrored symmetry), one can see that the site 1 of one monomer will be adjacent to site 2 on the other. In order to eliminate confusion, most literature refer to the binding sites across from site 1 and site 2 as site 2' and site 1', respectively. One of the most popular theories that is used to explain insulin binding describes that two molecules of insulin must bind to the IR in order for it to become active and for the kinase cascade to initiate. In this case, binding of two insulin molecules would occur at sites 1/2' and 2/1'. This is only a theory, however, and none of these theories have been completely confirmed [12].
Recent research has indicated that it may be possible that both the structure of the insulin receptor and the structure of insulin itself may change upon binding. It is also thought that insulin may possess multiple surfaces that are capable of binding to the functional ectodomain.
In order to better understand the binding of the insulin receptor, it would make sense to observe its main substrate, . This green scene shows both the hydrophobic and hydrophilic residues. The binding surface is mostly comprised of residues that are hydrophobic.
Another interesting point to mention is that insulin in its can also interact with the binding sites available on the insulin receptor. Hexamers of insulin are found in the pancreas and help store insulin. They consist of 3 insulin dimers that are held together by 2 Zn ions.Upon creating the hexamer form, a new binding surface for insulin is created that exhibits normal binding at site 1. Binding does not occur at site 2 however, and thus the hexamer form of insulin does not activate the insulin receptor as does regular form of insulin. Here is a that highlights the second binding surface. The second binding surface is highlighted on one of the three dimers and involves a small group of specific residues: SerA12, LeuA13, GluA17, HisB10, GluB13, and LeuB17 [13].
Additional Features
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