|
|
| Line 3: |
Line 3: |
| | <!-- INSERT YOUR SCENES AND TEXT BELOW THIS LINE --> | | <!-- INSERT YOUR SCENES AND TEXT BELOW THIS LINE --> |
| | | | |
| - | =='''Insulin Receptor'''== | + | |
| | + | =='''YourMacromolecule'''== |
| | | | |
| | ===Introduction=== | | ===Introduction=== |
| - | <Structure load='2dtg' size='500' frame='true' align='right' caption='Insulin receptors are expressed at the cell surface as disulfide-linked homodimers composed of alpha/beta monomers(pdb code 3loh).' scene='Sandbox_Reserved_427/Rcb_dimer_monomers/2' /> | + | <Structure load='1a84' size='300' frame='true' align='right' caption='pdbcode, Insert caption here' scene='Insert optional scene name here' /> |
| - | | + | <br><br><br><br><br><br><br><br><br><br><br><br><br><br><br><br><br><br><br><br> |
| - | The insulin receptor is a tyrosine kinase, that is a type of ligand-activated receptor kinase. The crystallized protein, shown here, is the <scene name='Sandbox_Reserved_427/Rcb_original_monomer/1'>ectodomain monomer</scene> 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 <scene name='Sandbox_Reserved_427/Rcb_dimer_betastrand/1'>bound</scene> to the membrane at the <span style="color:orange">'''beta strand'''</span>, 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.
| + | |
| - |
| + | |
| - | 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. <ref>PMID: 12471165</ref>
| + | |
| - | | + | |
| - | 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 <scene name='Sandbox_Reserved_427/Rcb_dimer_bindinghighlighted/1'>sites on the insulin receptor</scene>. The first binding insulin surface interacts with a site on the <span style="color:blue">'''L1'''</span> module as well as a 120-amino-acid peptide from the insert in <span style="color:red">'''FnIII-2'''</span>. The second binding site consists of resides on the C-terminal portion of <span style="color:aqua">'''L2'''</span> and in the <span style="color:fuchsia">'''FnIII-1'''</span> and <span style="color:red">'''FnIII-2'''</span> modules <ref>PMID: 2657531</ref>. Binding sites are shown <scene name='Sandbox_Reserved_427/Rcb_dimer_bindinghighlighted2/1'>here</scene> highlighted in both monomers of the biologically functional dimer. <ref>PMID: 18991400</ref>
| + | |
| - | | + | |
| - | 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.<ref>PMID: 12023989</ref> 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.<ref>PMID: 8326490</ref>
| + | |
| | | | |
| | ===Overall Structure=== | | ===Overall Structure=== |
| - | <Structure load='2dtg' size='500' frame='true' align='right' caption='The Different Domains of the Insulin Receptor Ectodomain' scene='Sandbox_Reserved_427/Ectodomain_dimer/1' /> | + | <Structure load='1a84' size='300' frame='true' align='right' caption='pdbcode, insert caption here' scene='Sandbox_Reserved_430/Intra-strand_phosphate/1' /> |
| - | | + | <br><br><br><br><br><br><br><br><br><br><br><br><br><br><br><br><br><br><br><br> |
| - | The ectodomain of the insulin receptor is a <scene name='Sandbox_Reserved_427/Ectodomain_dimer/1'>dimer</scene> of 2 identical monomers. Each v-shaped <scene name='Sandbox_Reserved_427/Kml_monomer6domain/1'>monomer</scene> is composed of 6 domains, three on each side of the V, shown in different colors. The <font color='red'>red</font> <scene name='Sandbox_Reserved_427/Kml_l1domain/1'>Leucine-rich repeat domain</scene> (<font color='red'>L1</font>) is involved in substrate binding. Its main feature is a 6 parallel stranded beta sheet. The <font color='orange'>orange</font> <scene name='Sandbox_Reserved_427/Kml_crdomain/1'>Cysteine-rich region</scene> (<font color='orange'>CR</font>) is composed mostly of loops and turns. The <font color='yellow'>yellow</font> domain is a second <scene name='Sandbox_Reserved_427/Kml_l2domain/1'>Leucine-rich repeat domain</scene>, (<font color='gold'>L2</font>) which contains a five parallel stranded beta sheet and several surface alpha helices. <ref>PMID: 16957736</ref>
| + | |
| - | | + | |
| - | 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.<ref>PMID: 2992939</ref> The <font color='lime'>green FnIII-1</font> <scene name='Sandbox_Reserved_427/Kml_fniii-1domain/1'>domain</scene>, contains one antiparallel and one mixed beta sheet. The <font color='mediumblue'>blue FnIII-2</font> <scene name='Sandbox_Reserved_427/Kml_fniii-2domain/2'>domain</scene> contains an <font color='deepskyblue'>insert</font> domain of 120 residues. The <font color='mediumorchid'>purple FnIII-3</font> <scene name='Sandbox_Reserved_427/Kml_fniii-3domain/1'>domain</scene> contains just four beta strands. Each domain occurs twice in the <scene name='Sandbox_Reserved_427/Ectodomain_dimer/2'>biological dimer</scene>.<ref>PMID: 16957736</ref>
| + | |
| - | | + | |
| - | The <font color='deepskyblue'>insert</font> domain of the <font color='mediumblue'>FnIII-2</font> domain separates the <font color='silver'>alpha</font> and '''beta''' chains of each monomer. The alpha chain contains the <font color='red'>L1</font>, <font color='orange'>CR</font>, <font color='yellow'>L2</font>, <font color='lime'>FnIII-1</font> domains and part of the <font color='mediumblue'>FnIII-2</font> domain. The beta chain contains the rest of the <font color='mediumblue'>FnIII-2</font> domain and the <font color='orchid'>FnIII-3</font> domain. The <font color='deepskyblue'>insert</font> domain starts and ends with a cleavage site where the chain is cut. The alpha and beta chains are then linked by a single <scene name='Sandbox_Reserved_427/Kl_disulphide/1'>disulphide bond</scene> between <font color='hotpink'>cysteines C647 and C860</font>, leaving the <font color='deepskyblue'>insert</font> domain as a separate peptide which forms disulphide bonds with cysteines in the <font color='lime'>FnIII-1</font> 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.<ref>PMID: 20348418</ref> This section of the beta chain, after the <font color='orchid'>FnIII-3</font> domain in the sequence, is not shown in the structure which reflects only the <scene name='Sandbox_Reserved_427/Ectodomain_dimer/2'>ectodomain</scene>. There are few interactions between the two legs of the monomer- just two salt bridges near the connection between the <font color='yellow'>L2</font> and <font color='lime'>FnIII-1</font> domains. However there are many interactions between the two monomers including salt bridges and disulphide bonds.<ref>PMID: 16957736</ref>
| + | |
| - | | + | |
| - | This structure is significant relative to previous structures for the protein because of the relative position of the <font color='red'>L1</font> domains in the two monomers of the biological unit. In previously proposed structures, the <font color='yellow'>L2</font>, <font color='orange'>CR</font>, and <font color='red'>L1</font> domains formed a straight leg of the V similar to that of the fibronectin leg. With this model, it was thought that both <font color='red'>L1</font> domains could bind to a single insulin molecule. With this folded over structure of the <font color='yellow'>L2</font>-<font color='orange'>CR</font>-<font color='red'>L1</font> leg, it is clear that this is not the case, as the <font color='red'>L1</font> domains of each monomer face away from each other.<ref>PMID: 16957736</ref>
| + | |
| | | | |
| | ===Binding Interactions=== | | ===Binding Interactions=== |
| - | <Structure load='2dtg' size='500' frame='true' align='right' caption='Depicted here is the monomer form of human insulin. The hydrophilic residues are shown in purple and the hydrophobic residues are shown in gray.' scene='Sandbox_Reserved_427/Insulin/2' /> | + | <Structure load='1a84' size='300' frame='true' align='right' caption='pdbcode, Insert caption here' scene='Insert optional scene name here' /> |
| - | 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.
| + | <br><br><br><br><br><br><br><br><br><br><br><br><br><br><br><br><br><br><br><br> |
| - | | + | |
| - | 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 <ref>PMID: 19274663</ref>.
| + | |
| - | | + | |
| - | 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, <scene name='Sandbox_Reserved_427/Insulin/2'>insulin</scene>. This green scene shows both the <font color='gray'>hydrophobic</font> and <font color='magenta'>hydrophilic</font> residues. The binding surface is mostly comprised of residues that are hydrophobic.
| + | |
| - | | + | |
| - | Another interesting point to mention is that insulin in its <scene name='Sandbox_Reserved_427/Insulin_hexamer/5'>hexamer form</scene> 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 <font color='red'>insulin dimers</font> that are held together by 2 <font color='blue'>Zn ions</font>.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 <scene name='Sandbox_Reserved_427/Insulin_hexamer_highlight/2'>green scene</scene> 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 <ref>PMID: 19274663</ref>.
| + | |
| | | | |
| | ===Additional Features=== | | ===Additional Features=== |
| - | <Structure load='2dtg' size='500' frame='true' align='right' caption='Shown above is the Insert Domain in green within the homodimer' scene='Sandbox_Reserved_427/Insert_domain/3' /> | + | <Structure load='1a84' size='300' frame='true' align='right' caption='pdbcode, Insert caption here' scene='Insert optional scene name here' /> |
| - | Interestingly, the molecular basis as to how insulin binds to the insulin receptor substrate (IRS) is not yet fully understood. However, there has been some light shed on the kinase cascade pathway that insulin induces.
| + | <br><br><br><br><br><br><br><br><br><br><br><br><br><br><br><br><br><br><br><br> |
| | | | |
| - | Recently, studies have shown that poor diet and increased sugar intake have led to a halt in the kinase cascade pathway, leading to what is now termed as insulin resistance.
| + | ===Quiz Question 1=== |
| | + | <Structure load='1a84' size='300' frame='true' align='right' caption='pdbcode, Insert caption here' scene='Insert optional scene name here' /> |
| | + | <br><br><br><br><br><br><br><br><br><br><br><br><br><br><br><br><br><br><br><br> |
| | | | |
| - | Insulin Resistance: Happens when the cells essentially don't open the door when insulin comes knocking. When this happens, the body puts out more insulin to stabilize blood glucose in the body. This allows for a vicious cycle where the cells become more and more desensitized as the concentration of insulin increases to tackle the constant influx of glucose. This occurs when the insulin receptor cannot activate the glucose transporter (Glut-4) vesicles through the kinase cascade in order for Glut-4 to bind to the cell membrane and bring in glucose. <ref>PMID:10675357</ref>
| + | ===Quiz Question 2=== |
| | + | <Structure load='1a84' size='300' frame='true' align='right' caption='pdbcode, Insert caption here' scene='Insert optional scene name here' /> |
| | + | <br><br><br><br><br><br><br><br><br><br><br><br><br><br><br><br><br><br><br><br> |
| | | | |
| - | Mechanism: When insulin binds it phosphorylates the IRS, leading to a kinase cascade pathway that ineveitably activates Glut-4 to bind to the cell membrane. Naturally, once the blood glucose has reached a normal level, the kinases are then dephosphorylated, which in turn slowly lowers the amount of glucose channels on the membrane surface. This is the normal negative feedback loop that takes place within the cell. However, when sugar intake is too high for too long, the amount of stored glucose (glycogen) will reach levels where the cell will try to stop the kinase pathway at any point necessary. At this point, the IRS will not be able to perform signal transduction even with the binding of insulin, proving insulin to be ineffective. In response to the increase in blood glucose, the Pancreas cranks out insulin in an attempt to lower blood glucose, when the binding interaction with IRS will essentially do nothing. In the end, all of the kinases become stuck in the dephosphorylated state even with high concentrations of insulin, and no glucose can be stored. The traffic jam will either kill the cell, or if glucose intake recedes, the cell can try to restore itself to its normal feedback loop. <ref>Zick, Y. ''Biochemical Society''. '''2004''', ''32'', 812-816</ref>
| + | ===Credits=== |
| | | | |
| - | So what's the cure?
| + | Introduction - name of team member |
| | | | |
| - | Extensive research has been conducted to see if the IRS can bind to other proteins which can then induce the kinase cascade pathway. In one experiment, the <scene name='Sandbox_Reserved_427/Insert_domain/3'>Insert Domain</scene> within the IRS has shown to exhibit binding to the active sites of the IRS. It does so through what has been hypothesized to be <scene name='Sandbox_Reserved_427/Trans_crosslinking/2'>trans crosslinking</scene> between the two monomers in the homodimer. The actual peptide connecting one piece of the insert domain to the other has yet to be resolved, however the binding portion of the insert domain has been <scene name='Sandbox_Reserved_427/Binding_site_of_insert_domain/1'>located</scene> to be at Site 1, between the <font color='red'>L1</font> and <font color='hotpink'>FnIII-2</font> domains. Since insulin binds to Site 1 as well, it is also hypothesized that the binding portion of the insert domain competitively binds with the insulin protein because of its mimical structure to insulin. This is quite an important discovery, because a compound that can mimic the structure of insulin could have a higher affinity for the IRS, which could activate the signal transduction pathway. Therefore, the IRS may provide a target for a drug, perhaps also achievable in part by molecules the size of antibiotics. <ref>PMID:20348418</ref>
| + | Overall Structure - name of team member |
| - | | + | |
| - | Best solution? Eat Healthy! Reducing sugar intake by eating less sweets should cause a break down of excess glycogen, returning cells to normal over time.
| + | |
| - | | + | |
| - | ===Credits===
| + | |
| | | | |
| - | Introduction - Rebecca Bishop
| + | Drug Binding Site - name of team member |
| | | | |
| - | Overall Structure - Kathryn Liedell
| + | Additional Features - name of team member |
| | | | |
| - | Drug Binding Site - Ryan Deeney
| + | Quiz Question 1 - name of team member |
| | | | |
| - | Additional Features - Jeffrey Boerth
| + | Quiz Question 2 - name of team member |
| | | | |
| | ===References=== | | ===References=== |
| | <references/> | | <references/> |
