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Revision as of 11:37, 25 March 2012

This Sandbox is Reserved from January 19, 2016, through August 31, 2016 for use for Proteopedia Team Projects by the class Chemistry 423 Biochemistry for Chemists taught by Lynmarie K Thompson at University of Massachusetts Amherst, USA. This reservation includes Sandbox Reserved 425 through Sandbox Reserved 439.

Contents 1 Insulin Receptor 1.1 Introduction 1.2 Overall Structure 1.3 Binding Interactions 1.4 Additional Features 1.5 Credits 1.6 References

Insulin Receptor

Introduction

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The insulin receptor is a tyrosine kinase, that is a type of ligand-activated receptor kinase. Insulin receptors are expressed at the cell surface as disulfide-linked homodimers composed of alpha/beta . The folded over conformation of the ectodomain places ligands in the correct relative positions for activity. The receptor 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. ^[1]

In everyday function, insulin receptor substrate 1 (IRS-1) 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 sites on the insulin receptor. The first binding insulin surface interacts with a site on the L1 module as well as a 12-amino-acid peptide from the insert in Fn2. The second binding site consists of resides on the C-terminal portion of L2 and in the Fn1 and Fn2 modules ^[2]. Binding sites are shown highlighted in both monomers of the biologically fuctional 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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-Ectodomain is a of 2 identical monomers (dimer green scene)

-Monomers composed of 6 domains (monomer green scene)

-Leucine-rich repeat domain (L1), secondary structures (green scene)

-Cystine-rich region (CR), secondary structures (green scene)

-Leucine-rich repeat domain (L2), secondary structures (green scene)

-Fibronectin Type III domain 1 (FnIII-1), secondary structures (green scene)

-Fibronectin Type III domain 2 (FnIII-2), secondary structures, insert domain (green scene)

-Fibronectin Type III domain 3 (FnIII-3), secondary structures (green scene)

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 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 ^[6].

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 posses multiple surfaces that are capable of binding to the functional ectodomain.

Another interesting point to mention is that insulin in its form can also interact with the binding sites available on the insulin receptor. Hexamers of insulin are found in the pancreas and help store insulin. Upon creating the hexameric 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 ^[7].

One source believes that the active site for the insulin receptor lies at this , which ranges approximately from Lys1085-Glu1208. The active site is displayed normally with the rest of the monomer faded out. Here is a green scene that depicts the location of the active site for the folded conformation of the insulin receptor. . The active sites are highlighted in green ^[8].

Additional Features

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Interestingly, the molecular basis as to how binds to the insulin receptor substrate (IRS) remains elusive. However, there has been some light shed on the kinase cascade pathway that insulin induces.

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.

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 (Glu-4) vesicles to bind to the membrane in order to bring in glucose. ^[9]

Mechanism: When Insulin binds it induces phosphorylation of the IRS, leading to a kinase cascade pathway that ineveitably activates Glu-4. Naturally, once the blood glucose has reached a normal level, the kinases are then dephosphorylated, which in turn slowly lower than amount of the glucose channels on the membrane surface. This is the normal negative feedback loop. However, when sugar intake is too high for too long, the amount of stored glucose (glycogen) will reach its maximum capacity. The cell will not take in anymore glucose, which raises blood glucose levels. In response, 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 phosphorylated state from the high concentration of insulin, but 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. ^[10]

So what's the cure?

Extensive research has been conducted to see if the IRS can bind to other proteins which can then induce similar but not the same kinase cascades. The within the receptor homodimer may provide a target for the design of nonpeptide agonists, perhaps achievable in part by molecules the size of antibiotics and could be “druggable.” ^[11]

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

Overall Structure - Kathryn Liedell

Drug Binding Site - Ryan Deeney

Additional Features - Jeffrey Boerth

I suggest that one of you show us what insulin looks like and which are thought to be the binding surfaces on insulin and on the receptor. Prof T -->I think I can work that into the intro. Bec I remember saying I could add the insulin green scene in. If you'd like to add it Bec it's not a big deal, I'd just like to have at least two green scenes. -Jeff I'll also be adding another green scene that involves insulin in my section. I think that we'll all be mentioning it in our sections. - Ryan. Jeff I am pretty happy with my section is, does that duplicate what you wanted to do too much? - Bec

References

1. ↑ Kitamura T, Kahn CR, Accili D. Insulin receptor knockout mice. Annu Rev Physiol. 2003;65:313-32. Epub 2002 May 1. PMID:12471165 doi:10.1146/annurev.physiol.65.092101.142540
2. ↑ Fried R. A literary look at contemporary society. Ohio Med. 1989 May;85(5):393-5. PMID:2657531
3. ↑ Whittaker L, Hao C, Fu W, Whittaker J. High-affinity insulin binding: insulin interacts with two receptor ligand binding sites. Biochemistry. 2008 Dec 2;47(48):12900-9. PMID:18991400 doi:10.1021/bi801693h
4. ↑ Longo N, Wang Y, Smith SA, Langley SD, DiMeglio LA, Giannella-Neto D. Genotype-phenotype correlation in inherited severe insulin resistance. Hum Mol Genet. 2002 Jun 1;11(12):1465-75. PMID:12023989
5. ↑ al-Gazali LI, Khalil M, Devadas K. A syndrome of insulin resistance resembling leprechaunism in five sibs of consanguineous parents. J Med Genet. 1993 Jun;30(6):470-5. PMID:8326490
6. ↑ Ward CW, Lawrence MC. Ligand-induced activation of the insulin receptor: a multi-step process involving structural changes in both the ligand and the receptor. Bioessays. 2009 Apr;31(4):422-34. PMID:19274663 doi:10.1002/bies.200800210
7. ↑ Ward CW, Lawrence MC. Ligand-induced activation of the insulin receptor: a multi-step process involving structural changes in both the ligand and the receptor. Bioessays. 2009 Apr;31(4):422-34. PMID:19274663 doi:10.1002/bies.200800210
8. ↑ Ablooglu AJ, Frankel M, Rusinova E, Ross JB, Kohanski RA. Multiple activation loop conformations and their regulatory properties in the insulin receptor's kinase domain. J Biol Chem. 2001 Dec 14;276(50):46933-40. Epub 2001 Oct 11. PMID:11598120 doi:10.1074/jbc.M107236200
9. ↑ Cusi K, Maezono K, Osman A, Pendergrass M, Patti ME, Pratipanawatr T, DeFronzo RA, Kahn CR, Mandarino LJ. Insulin resistance differentially affects the PI 3-kinase- and MAP kinase-mediated signaling in human muscle. J Clin Invest. 2000 Feb;105(3):311-20. PMID:10675357 doi:10.1172/JCI7535
10. ↑ Zick, Y. Biochemical Society. 2004, 32, 812-816
11. ↑ Smith BJ, Huang K, Kong G, Chan SJ, Nakagawa S, Menting JG, Hu SQ, Whittaker J, Steiner DF, Katsoyannis PG, Ward CW, Weiss MA, Lawrence MC. Structural resolution of a tandem hormone-binding element in the insulin receptor and its implications for design of peptide agonists. Proc Natl Acad Sci U S A. 2010 Apr 13;107(15):6771-6. Epub 2010 Mar 26. PMID:20348418