National institutes of health nih in bethesda, maryland, as a fogarty international fellow. This structure unexpectedly reveals that maximally four insulins can bind the tshaped. During the past several years, significant progress has been made toward elucidating the subunit structure of the insulin receptor using a variety of techniques 17. Signal transduction through the insulin receptor appears to require the activation of an intrinsic tyrosinespecific protein kinase activity. Structure short article higherresolution structure of the human insulin receptor ectodomain. Multimodal inclusion of the insert domain tristan i. Cryoem structure of the complete and ligandsaturated. The insulin receptor is a member of the ligandactivated receptor and tyrosine kinase family of transmembrane signaling proteins that collectively are fundamentally important regulators of cell differentiation, growth, and metabolism. The structure of insulin receptor and its subunits. The insulin receptor plays a key role in many physiological processes, yet how insulin effects receptor signaling at the structural level remains incomplete. Activation mechanism of the insulin receptor revealed by cryo.
The insulin receptor has a number of unique physiological and biochemical properties that distinguish it from other members of this large wellstudied receptor family. Here, we report the cryoem structure of fulllength insulin receptor ir and insulin complex in the active state. Goldlabeled insulin served to locate the insulin binding domain. In particular, ir overactivation by igfii is common in cancer cells, especially in dedifferentiatedstemlike cells. Insr insulin receptor precursor homo sapiens human. It moves quickly through the blood and is easily captured by receptors on cell surfaces, delivering its message. When insulin binds to the receptor, the conformation of insulin receptor. Solution structure of ectodomains of the insulin receptor family. Sequences of the insulin receptor ir, the typei insulinlike growthfactor receptor igfr and the insulinreceptorrelated receptor show that they belong to a homologous family but, until. Using a combined approach of cryoem and atomistic molecular dynamics simulation, we present the structure of the entire dimeric insulin receptor ectodomain saturated with four insulin molecules.
A large body of evidences have shown that both the igfi receptor igfir and the insulin receptor ir play a role in cancer development and progression. All data generated or analysed during this study are included in the manuscript and supporting files. The insulin receptor is a heterotetrameric glycoprotein consisting oftwoasubunits ofmr 5,000andtwo3subunits ofmr 95,000 linked by disulfide bonds to give a,3aa structure 8, 9 fig. Activation mechanism of the insulin receptor revealed. Evidence for multiple nonreduced forms and a 210,000 possible proreceptor. The insulin receptor is a glycoprotein with molecular weight of about 300 kda. Receptor tyrosine kinases are allosterically regulated by their cognate ligands and function as dimers. Insulin receptor substrate signaling controls cardiac. This article will consider the structure of insulin, how it is synthesised and secreted, its actions on the body and clinical conditions that are associated with faults in its production. Pdf recently, major progress has been made in uncovering the mechanisms of how insulin engages its receptor and modulates downstream.
Insulin receptor structure and its implications for the igf1 receptor. In addition, the discovery that the insulin receptor structure is associated with tyrosine kinase activity has led to detailed enzymological studies of this receptor. Structure of the insulin receptorinsulin complex by single. In all cases but the insulin receptor and 2 closely related receptors, these dimers are noncovalent, but insulin receptors are covalently maintained as functional dimers by disulfide bonds. It is responsible for regulating movement of glucose from the blood into cells. Activation mechanism of the insulin receptor revealed by. It is a 1 kda protein with amino acid sequence of 1242 residues. The structure and function of the insulin receptor has been the subject of intensive research effort in the last few years. Goldlabeled insulin served to locate the insulinbinding domain. The 3d structure was then fitted with available known highresolution domain substructures to obtain a detailed contiguous model for this heterotetrameric transmembrane.
The primary translation product of the insulin receptor mrna is a linear alphabeta sequence of the insulin receptor precursor proreceptor. The solution of the three dimensional structure of insulin in 1969 provided a. Oct 24, 2018 the insulin receptor plays a key role in many physiological processes, yet how insulin effects receptor signaling at the structural level remains incomplete. Insulin receptor structure and function in normal and pathological conditions andrew b. The potential link between insulin receptor signaling malfunction and neurological disorders will also be discussed.
Upon insulin binding, the ectodomain of the receptor undergoes a dramatic reorganization, changing from a ushaped to a tshaped structure and also causing a rearrangement of the transmembrane. Insulin activates the insulin receptor tyrosine kinase ir, which phosphorylates and recruits different substrate adaptors such as the irs family of proteins. Insulin is the major hormone controlling critical energy functions such as glucose and lipid metabolism. Structural determinants of the insulin receptorrelated receptor. The receptors for insulin and igfl are trans membrane, heterotetrameric glycoprotein structures that possess ligand binding sites in the extracellular u. Aug 22, 2019 insulin receptor ir is a receptor tyrosine kinase rtk that plays essential roles in glucose metabolism and cell growth ullrich et al. The actions of insulin are mediated by an integral plasma membrane protein, the insulin receptor. The main physiological role of the insulin receptor appears to be metabolic regulation, whereas all other receptor. Metabolically, the insulin receptor plays a key role in the regulation of glucose homeostasis, a functional process that under degenerate conditions may result in a range of clinical manifestations including diabetes and cancer.
Pilch recently developed affinitylabeling techniques have been used to study the subunit com position and stoichiometrv of the insulin receptor. Insulin receptor ir is a 2type receptor tyrosine kinase that plays a. Promising progress in understanding the molecular basis of insulin action has been achieved by demonstrating that the insulin receptor is an insulinsensitive tyrosine kinase. The structure of the glial insulin receptor subunits was assessed by affinity crosslinking of 125iinsulin with the alphasubunit of the receptor, neuraminidase treatment of the crosslinked receptor, behavior of the receptor on lectin columns, and electrophoretic mobility of the phosphorylated betasubunit. Increased glut especially 4 expression on cell surfaces. Crytstal structure of the activated insulin receptor tryosine kinase in complex with peptide substrate and atp analog. Pdf structure and dynamics of the insulin receptor. Insulin receptor substrate 1 irs1 is a signaling adapter protein that in humans is encoded by the irs1 gene. The rasrafmap2kmapk pathway is mainly involved in mediating cell growth, survival and cellular differentiation of insulin. The insulin receptor is a large cell surface glycoprotein that concentrates insulin at the site of action and also initiates responses to insulin.
In spite of these findings, until very recently, only igfir but not ir has been considered a target in cancer therapy. Dendritic structure not only determines which axons are potential presynaptic partners, but also determines how the inputs are integrated. Irr is a member of the insulin receptor ir family that does not have any known. The insulin proreceptor cdna has been cloned and its complete amino acid sequence deduced. Insulin receptor signaling in the development of neuronal structure and function 117 4. Pdf solution structure of ectodomains of the insulin. Higherresolution structure of the human insulin receptor.
The endosomal apparatus j j m bergeron, j cruz, m n khan, and. From these studies it appears that the insulin receptor is composed of two. Complementing the previously described insulinsite 1 interaction, we present the first view of insulin bound to the discrete insulin receptor site 2. Insulin receptor has been purified by affinity chromatography and studied by affinity labeling techniques. Insulin is a protein composed of two chains, an a chain with 21 amino acids and a b chain with 30 amino acids, which are linked together by sulfur atoms. Phosphorylated irs1 recruits grb2sos complex, which triggers the activation of the rasrafmap2kmapk pathway. Quaternary structure of the insulininsulin receptor. Cryoem maps and the corresponding bulit models of insulin receptorinsulin complex have been deposited in emdb and pdb under the accession codes emd20522emd20523 and 6pxv6pxw, respectively. Insulin receptor structure and function in normal and. Aug 22, 2019 cryoem maps and the corresponding bulit models of insulin receptor insulin complex have been deposited in emdb and pdb under the accession codes emd20522emd20523 and 6pxv6pxw, respectively. The ectodomain of the type 1 insulin like growth factor receptor displays asymmetry of ligand binding accompanied by limited conformational change. This article will consider the structure of insulin, how it is synthesised and secreted, its actions on the body and clinical conditions that.
When blood glucose levels rise, insulin released by the betacells of the pancreas binds to the insulin receptor on muscle cells andor adipocytes and facilitated dimerisation of the receptor. The processed receptor is a tetramer composed of two. Unlike most rtks, ir forms a stable homodimer covalently linked by multiple disulfide bonds schaffer and ljungqvist, 1992. The insulin receptor and the molecular mechanism of. Sequences of the insulin receptor ir, the typei insulin like growthfactor receptor igfr and the insulin receptor related receptor show that they belong to a homologous family but, until. Quaternary structure of the insulininsulin receptor complex. The receptor is a disulfidelinked oligomer comprised of two. The insulin receptor ir is a transmembrane receptor that is activated by insulin, igfi, igfii and belongs to the large class of tyrosine kinase receptors. Proinsulin is relatively inactive, and under normal conditions only a small amount of it is secreted. The ectodomain of the type 1 insulinlike growth factor receptor displays asymmetry of ligand binding accompanied by limited conformational change. Structure and function of insulin receptors diabetes. Insulin receptor signaling cell signaling technology. The signal sequence of 27 hydrophobic amino acids at the nterminus of the alphasubunit allows the receptor to enter the endoplasmic reticulum, during which process the signal peptide is cleaved. Insulin receptor signaling in the development of neuronal.
Structure of the insulin receptorinsulin complex by. Promising progress in understanding the molecular basis of insulin action has been achieved by demonstrating that the insulin receptor is an insulin sensitive tyrosine kinase. The insulin receptor serves to not only concentrate insulin on the appropriate target cells, but also to initiate the responses of these cells to the hormone. Theasubunitappearsto be entirely extracellular and contains the insulin binding site. The details are still a mystery and an area of active research. Insulin is derived from a 74aminoacid prohormone molecule called proinsulin. When insulin binds to the receptor, it is thought to cause a change in shape that is propagated inside the cell, activating the tyrosine kinases. Insulin receptor ir is a receptor tyrosine kinase rtk that plays essential roles in glucose metabolism and cell growth ullrich et al. Structure and function of the insulin receptora personal. The achain of insulin contacts the insert domain of the insulin receptor. Pdf promising progress in understanding the molecular basis of insulin action has been achieved by demonstrating that the insulin receptor. Dysregulation of ir signaling is linked to many human diseases, such as diabetes and cancers olefsky, 1976. The structure of the glial insulin receptor subunits was assessed by affinity crosslinking of 125i insulin with the alphasubunit of the receptor, neuraminidase treatment of the crosslinked receptor, behavior of the receptor on lectin columns, and electrophoretic mobility of the phosphorylated betasubunit. Thisbinding site canbeaffinity labeled using labeled insulin.
The insulin receptor is a dimeric protein that has a crucial role in controlling glucose homeostasis, regulating lipid, protein and carbohydrate metabolism, and modulating brain neurotransmitter. Regulation of insulin receptor gene expression cell cyclemediated effects on insulin receptor mrna stability received for publication, july 7, 1992 james r. Insulin receptor ir signaling is critical to controlling nutrient uptake and metabolism. It contains a single pleckstrin homology ph domain at the nterminus and a ptb domain ca. Structural basis for the lower affinity of the insulinlike growth factors for the insulin receptor. Get a printable copy pdf file of the complete article 1. A recent structure of insulin bound to a portion of the receptor insulin shown here in red from pdb entry 3w14 places another piece. Journal of biological chemistry 2008, 283 5, 260426. In addition to binding insulin, the insulin receptor can bind insulinlike growth factors igfi and igfii. After insulin has bound to insulin receptor insr, what are some of the effects that the insulin receptor substrates irs go on to have.
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