Insulin receptor

Last updated

INSR
IR Ectodomain mod3LOH.png
Available structures
PDB Ortholog search: PDBe RCSB
Identifiers
Aliases INSR , CD220, HHF5, insulin receptor
External IDs OMIM: 147670; MGI: 96575; HomoloGene: 20090; GeneCards: INSR; OMA:INSR - orthologs
Orthologs
SpeciesHumanMouse
Entrez

3643

16337

Ensembl

ENSG00000171105

ENSMUSG00000005534

UniProt

P06213

P15208

RefSeq (mRNA)

NM_000208
NM_001079817

NM_010568
NM_001330056

RefSeq (protein)

NP_000199
NP_001073285

NP_001316985
NP_034698

Location (UCSC) Chr 19: 7.11 – 7.29 Mb Chr 8: 3.17 – 3.33 Mb
PubMed search [3] [4]
Wikidata
View/Edit Human View/Edit Mouse

The insulin receptor (IR) is a transmembrane receptor that is activated by insulin, IGF-I, IGF-II and belongs to the large class of receptor tyrosine kinase. [5] 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. [6] [7] Insulin signalling controls access to blood glucose in body cells. When insulin falls, especially in those with high insulin sensitivity, body cells begin only to have access to lipids that do not require transport across the membrane. So, in this way, insulin is the key regulator of fat metabolism as well. Biochemically, the insulin receptor is encoded by a single gene INSR , from which alternate splicing during transcription results in either IR-A or IR-B isoforms. [8] Downstream post-translational events of either isoform result in the formation of a proteolytically cleaved α and β subunit, which upon combination are ultimately capable of homo or hetero-dimerisation to produce the ≈320 kDa disulfide-linked transmembrane insulin receptor. [8]

Structure

Initially, transcription of alternative splice variants derived from the INSR gene are translated to form one of two monomeric isomers; IR-A in which exon 11 is excluded, and IR-B in which exon 11 is included. Inclusion of exon 11 results in the addition of 12 amino acids upstream of the intrinsic furin proteolytic cleavage site.

Colour-coded schematic of the insulin receptor Colour coded Schematic of the Insulin Receptor.png
Colour-coded schematic of the insulin receptor

Upon receptor dimerisation, after proteolytic cleavage into the α- and β-chains, the additional 12 amino acids remain present at the C-terminus of the α-chain (designated αCT) where they are predicted to influence receptor–ligand interaction. [9]

Each isometric monomer is structurally organized into 8 distinct domains consists of; a leucine-rich repeat domain (L1, residues 1–157), a cysteine-rich region (CR, residues 158–310), an additional leucine rich repeat domain (L2, residues 311–470), three fibronectin type III domains; FnIII-1 (residues 471–595), FnIII-2 (residues 596–808) and FnIII-3 (residues 809–906). Additionally, an insert domain (ID, residues 638–756) resides within FnIII-2, containing the α/β furin cleavage site, from which proteolysis results in both IDα and IDβ domains. Within the β-chain, downstream of the FnIII-3 domain lies a transmembrane helix (TH) and intracellular juxtamembrane (JM) region, just upstream of the intracellular tyrosine kinase (TK) catalytic domain, responsible for subsequent intracellular signaling pathways. [10]

Upon cleavage of the monomer to its respective α- and β-chains, receptor hetero or homo-dimerisation is maintained covalently between chains by a single disulphide link and between monomers in the dimer by two disulphide links extending from each α-chain. The overall 3D ectodomain structure, possessing four ligand binding sites, resembles an inverted 'V', with the each monomer rotated approximately 2-fold about an axis running parallel to the inverted 'V' and L2 and FnIII-1 domains from each monomer forming the inverted 'V's apex. [10] [11]

Ligand binding

Ligand-induced conformation changes in the full-length human insulin receptor reconstituted in nanodiscs. Left - unactivated receptor conformation; right - insulin-activated receptor conformation. The changes are visualized with the electron microscopy of an individual molecule (upper panel) and schematically depicted as a cartoon (lower panel). Insulin receptor conformation change upon binding-scheme.jpg
Ligand-induced conformation changes in the full-length human insulin receptor reconstituted in nanodiscs. Left - unactivated receptor conformation; right - insulin-activated receptor conformation. The changes are visualized with the electron microscopy of an individual molecule (upper panel) and schematically depicted as a cartoon (lower panel).
Left - cryo-EM structure of the ligand-saturated IR ectodomain; right - 4 binding sites and IR structure upon binding schematically depicted as a cartoon. Ligand-saturated-cryoEM-IR-structure.png
Left - cryo-EM structure of the ligand-saturated IR ectodomain; right - 4 binding sites and IR structure upon binding schematically depicted as a cartoon.

The insulin receptor's endogenous ligands include insulin, IGF-I and IGF-II. Using a cryo-EM, structural insight into conformational changes upon insulin binding was provided. Binding of ligand to the α-chains of the IR dimeric ectodomain shifts it from an inverted V-shape to a T-shaped conformation, and this change is propagated structurally to the transmembrane domains, which get closer, eventually leading to autophosphorylation of various tyrosine residues within the intracellular TK domain of the β-chain. [12] These changes facilitate the recruitment of specific adapter proteins such as the insulin receptor substrate proteins (IRS) in addition to SH2-B (Src Homology 2 - B ), APS and protein phosphatases, such as PTP1B, eventually promoting downstream processes involving blood glucose homeostasis. [14]

Strictly speaking the relationship between IR and ligand shows complex allosteric properties. This was indicated with the use of a Scatchard plots which identified that the measurement of the ratio of IR bound ligand to unbound ligand does not follow a linear relationship with respect to changes in the concentration of IR bound ligand, suggesting that the IR and its respective ligand share a relationship of cooperative binding. [15] Furthermore, the observation that the rate of IR-ligand dissociation is accelerated upon addition of unbound ligand implies that the nature of this cooperation is negative; said differently, that the initial binding of ligand to the IR inhibits further binding to its second active site - exhibition of allosteric inhibition. [15]

These models state that each IR monomer possesses 2 insulin binding sites; site 1, which binds to the 'classical' binding surface of insulin: consisting of L1 plus αCT domains and site 2, consisting of loops at the junction of FnIII-1 and FnIII-2 predicted to bind to the 'novel' hexamer face binding site of insulin. [5] As each monomer contributing to the IR ectodomain exhibits 3D 'mirrored' complementarity, N-terminal site 1 of one monomer ultimately faces C-terminal site 2 of the second monomer, where this is also true for each monomers mirrored complement (the opposite side of the ectodomain structure). Current literature distinguishes the complement binding sites by designating the second monomer's site 1 and site 2 nomenclature as either site 3 and site 4 or as site 1' and site 2' respectively. [5] [14] As such, these models state that each IR may bind to an insulin molecule (which has two binding surfaces) via 4 locations, being site 1, 2, (3/1') or (4/2'). As each site 1 proximally faces site 2, upon insulin binding to a specific site, 'crosslinking' via ligand between monomers is predicted to occur (i.e. as [monomer 1 Site 1 - Insulin - monomer 2 Site (4/2')] or as [monomer 1 Site 2 - Insulin - monomer 2 site (3/1')]). In accordance with current mathematical modelling of IR-insulin kinetics, there are two important consequences to the events of insulin crosslinking; 1. that by the aforementioned observation of negative cooperation between IR and its ligand that subsequent binding of ligand to the IR is reduced and 2. that the physical action of crosslinking brings the ectodomain into such a conformation that is required for intracellular tyrosine phosphorylation events to ensue (i.e. these events serve as the requirements for receptor activation and eventual maintenance of blood glucose homeostasis). [14]

Applying cryo-EM and molecular dynamics simulations of receptor reconstituted in nanodiscs, the structure of the entire dimeric insulin receptor ectodomain with four insulin molecules bound was visualized, therefore confirming and directly showing biochemically predicted 4 binding locations. [13]

Agonists

A number of small-molecule insulin receptor agonists have been identified. [16]

Signal transduction pathway

The insulin receptor is a type of tyrosine kinase receptor, in which the binding of an agonistic ligand triggers autophosphorylation of the tyrosine residues, with each subunit phosphorylating its partner. The addition of the phosphate groups generates a binding site for the insulin receptor substrate (IRS-1), which is subsequently activated via phosphorylation. The activated IRS-1 initiates the signal transduction pathway and binds to phosphoinositide 3-kinase (PI3K), in turn causing its activation. This then catalyses the conversion of Phosphatidylinositol 4,5-bisphosphate into Phosphatidylinositol 3,4,5-trisphosphate (PIP3). PIP3 acts as a secondary messenger and induces the activation of phosphatidylinositol dependent protein kinase, which then activates several other kinases – most notably protein kinase B, (PKB, also known as Akt). PKB triggers the translocation of glucose transporter (GLUT4) containing vesicles to the cell membrane, via the activation of SNARE proteins, to facilitate the diffusion of glucose into the cell. PKB also phosphorylates and inhibits glycogen synthase kinase, which is an enzyme that inhibits glycogen synthase. Therefore, PKB acts to start the process of glycogenesis, which ultimately reduces blood-glucose concentration. [17]

Function

Regulation of gene expression

The activated IRS-1 acts as a secondary messenger within the cell to stimulate the transcription of insulin-regulated genes. First, the protein Grb2 binds the P-Tyr residue of IRS-1 in its SH2 domain. Grb2 is then able to bind SOS, which in turn catalyzes the replacement of bound GDP with GTP on Ras, a G protein. This protein then begins a phosphorylation cascade, culminating in the activation of mitogen-activated protein kinase (MAPK), which enters the nucleus and phosphorylates various nuclear transcription factors (such as Elk1).

Stimulation of glycogen synthesis

Glycogen synthesis is also stimulated by the insulin receptor via IRS-1. In this case, it is the SH2 domain of PI-3 kinase (PI-3K) that binds the P-Tyr of IRS-1. Now activated, PI-3K can convert the membrane lipid phosphatidylinositol 4,5-bisphosphate (PIP2) to phosphatidylinositol 3,4,5-triphosphate (PIP3). This indirectly activates a protein kinase, PKB (Akt), via phosphorylation. PKB then phosphorylates several target proteins, including glycogen synthase kinase 3 (GSK-3). GSK-3 is responsible for phosphorylating (and thus deactivating) glycogen synthase. When GSK-3 is phosphorylated, it is deactivated, and prevented from deactivating glycogen synthase. In this roundabout manner, insulin increases glycogen synthesis.

Degradation of insulin

Once an insulin molecule has docked onto the receptor and effected its action, it may be released back into the extracellular environment or it may be degraded by the cell. Degradation normally involves endocytosis of the insulin-receptor complex followed by the action of insulin degrading enzyme. Most insulin molecules are degraded by liver cells. It has been estimated that a typical insulin molecule is finally degraded about 71 minutes after its initial release into circulation. [18]

Immune system

Besides the metabolic function, insulin receptors are also expressed on immune cells, such as macrophages, B cells, and T cells. On T cells, the expression of insulin receptors is undetectable during the resting state but up-regulated upon T-cell receptor (TCR) activation. Indeed, insulin has been shown when supplied exogenously to promote in vitro T cell proliferation in animal models. Insulin receptor signalling is important for maximizing the potential effect of T cells during acute infection and inflammation. [19] [20]

Pathology

The main activity of activation of the insulin receptor is inducing glucose uptake. For this reason "insulin insensitivity", or a decrease in insulin receptor signaling, leads to diabetes mellitus type 2 – the cells are unable to take up glucose, and the result is hyperglycemia (an increase in circulating glucose), and all the sequelae that result from diabetes.

Patients with insulin resistance may display acanthosis nigricans.

A few patients with homozygous mutations in the INSR gene have been described, which causes Donohue syndrome or Leprechaunism. This autosomal recessive disorder results in a totally non-functional insulin receptor. These patients have low-set, often protuberant, ears, flared nostrils, thickened lips, and severe growth retardation. In most cases, the outlook for these patients is extremely poor, with death occurring within the first year of life. Other mutations of the same gene cause the less severe Rabson-Mendenhall syndrome, in which patients have characteristically abnormal teeth, hypertrophic gingiva (gums), and enlargement of the pineal gland. Both diseases present with fluctuations of the glucose level: After a meal the glucose is initially very high, and then falls rapidly to abnormally low levels. [21] Other genetic mutations to the insulin receptor gene can cause Severe Insulin Resistance. [22]

Interactions

Insulin receptor has been shown to interact with

Related Research Articles

<span class="mw-page-title-main">Protein kinase</span> Enzyme that adds phosphate groups to other proteins

A protein kinase is a kinase which selectively modifies other proteins by covalently adding phosphates to them (phosphorylation) as opposed to kinases which modify lipids, carbohydrates, or other molecules. Phosphorylation usually results in a functional change of the target protein (substrate) by changing enzyme activity, cellular location, or association with other proteins. The human genome contains about 500 protein kinase genes and they constitute about 2% of all human genes. There are two main types of protein kinase. The great majority are serine/threonine kinases, which phosphorylate the hydroxyl groups of serines and threonines in their targets. Most of the others are tyrosine kinases, although additional types exist. Protein kinases are also found in bacteria and plants. Up to 30% of all human proteins may be modified by kinase activity, and kinases are known to regulate the majority of cellular pathways, especially those involved in signal transduction.

<span class="mw-page-title-main">Tyrosine kinase</span> Enzyme

A tyrosine kinase is an enzyme that can transfer a phosphate group from ATP to the tyrosine residues of specific proteins inside a cell. It functions as an "on" or "off" switch in many cellular functions.

The JAK-STAT signaling pathway is a chain of interactions between proteins in a cell, and is involved in processes such as immunity, cell division, cell death, and tumour formation. The pathway communicates information from chemical signals outside of a cell to the cell nucleus, resulting in the activation of genes through the process of transcription. There are three key parts of JAK-STAT signalling: Janus kinases (JAKs), signal transducer and activator of transcription proteins (STATs), and receptors. Disrupted JAK-STAT signalling may lead to a variety of diseases, such as skin conditions, cancers, and disorders affecting the immune system.

<span class="mw-page-title-main">Receptor tyrosine kinase</span> Class of enzymes

Receptor tyrosine kinases (RTKs) are the high-affinity cell surface receptors for many polypeptide growth factors, cytokines, and hormones. Of the 90 unique tyrosine kinase genes identified in the human genome, 58 encode receptor tyrosine kinase proteins. Receptor tyrosine kinases have been shown not only to be key regulators of normal cellular processes but also to have a critical role in the development and progression of many types of cancer. Mutations in receptor tyrosine kinases lead to activation of a series of signalling cascades which have numerous effects on protein expression. The receptors are generally activated by dimerization and substrate presentation. Receptor tyrosine kinases are part of the larger family of protein tyrosine kinases, encompassing the receptor tyrosine kinase proteins which contain a transmembrane domain, as well as the non-receptor tyrosine kinases which do not possess transmembrane domains.

<span class="mw-page-title-main">Platelet-derived growth factor receptor</span> Cell surface receptors

Platelet-derived growth factor receptors (PDGF-R) are cell surface tyrosine kinase receptors for members of the platelet-derived growth factor (PDGF) family. PDGF subunits -A and -B are important factors regulating cell proliferation, cellular differentiation, cell growth, development and many diseases including cancer. There are two forms of the PDGF-R, alpha and beta each encoded by a different gene. Depending on which growth factor is bound, PDGF-R homo- or heterodimerizes.

<span class="mw-page-title-main">GRB2</span> Protein-coding gene in the species Homo sapiens

Growth factor receptor-bound protein 2, also known as Grb2, is an adaptor protein involved in signal transduction/cell communication. In humans, the GRB2 protein is encoded by the GRB2 gene.

<span class="mw-page-title-main">PTPN11</span> Protein-coding gene in humans

Tyrosine-protein phosphatase non-receptor type 11 (PTPN11) also known as protein-tyrosine phosphatase 1D (PTP-1D), Src homology region 2 domain-containing phosphatase-2 (SHP-2), or protein-tyrosine phosphatase 2C (PTP-2C) is an enzyme that in humans is encoded by the PTPN11 gene. PTPN11 is a protein tyrosine phosphatase (PTP) Shp2.

<span class="mw-page-title-main">GRB10</span> Protein-coding gene in the species Homo sapiens

Growth factor receptor-bound protein 10 also known as insulin receptor-binding protein Grb-IR is a protein that in humans is encoded by the GRB10 gene.

A growth factor receptor is a receptor that binds to a growth factor. Growth factor receptors are the first stop in cells where the signaling cascade for cell differentiation and proliferation begins. Growth factors, which are ligands that bind to the receptor are the initial step to activating the growth factor receptors and tells the cell to grow and/or divide.

The ErbB family of proteins contains four receptor tyrosine kinases, structurally related to the epidermal growth factor receptor (EGFR), its first discovered member. In humans, the family includes Her1, Her2 (ErbB2), Her3 (ErbB3), and Her4 (ErbB4). The gene symbol, ErbB, is derived from the name of a viral oncogene to which these receptors are homologous: erythroblastic leukemia viral oncogene. Insufficient ErbB signaling in humans is associated with the development of neurodegenerative diseases, such as multiple sclerosis and Alzheimer's disease, while excessive ErbB signaling is associated with the development of a wide variety of types of solid tumor.

<span class="mw-page-title-main">Insulin receptor substrate 1</span> Protein found in humans

Insulin receptor substrate 1(IRS-1) is a signaling adapter protein that in humans is encoded by the IRS1 gene. It is a 180 kDa protein with amino acid sequence of 1242 residues. It contains a single pleckstrin homology (PH) domain at the N-terminus and a PTB domain ca. 40 residues downstream of this, followed by a poorly conserved C-terminus tail. Together with IRS2, IRS3 (pseudogene) and IRS4, it is homologous to the Drosophila protein chico, whose disruption extends the median lifespan of flies up to 48%. Similarly, Irs1 mutant mice experience moderate life extension and delayed age-related pathologies.

<span class="mw-page-title-main">NCK1</span> Protein-coding gene in the species Homo sapiens

Cytoplasmic protein NCK1 is a protein that in humans is encoded by the NCK1 gene.

The Akt signaling pathway or PI3K-Akt signaling pathway is a signal transduction pathway that promotes survival and growth in response to extracellular signals. Key proteins involved are PI3K and Akt.

A non-receptor tyrosine kinase (nRTK) is a cytosolic enzyme that is responsible for catalysing the transfer of a phosphate group from a nucleoside triphosphate donor, such as ATP, to tyrosine residues in proteins. Non-receptor tyrosine kinases are a subgroup of protein family tyrosine kinases, enzymes that can transfer the phosphate group from ATP to a tyrosine residue of a protein (phosphorylation). These enzymes regulate many cellular functions by switching on or switching off other enzymes in a cell.

<span class="mw-page-title-main">Cell surface receptor</span> Class of ligand activated receptors localized in surface of plama cell membrane

Cell surface receptors are receptors that are embedded in the plasma membrane of cells. They act in cell signaling by receiving extracellular molecules. They are specialized integral membrane proteins that allow communication between the cell and the extracellular space. The extracellular molecules may be hormones, neurotransmitters, cytokines, growth factors, cell adhesion molecules, or nutrients; they react with the receptor to induce changes in the metabolism and activity of a cell. In the process of signal transduction, ligand binding affects a cascading chemical change through the cell membrane.

Src kinase family is a family of non-receptor tyrosine kinases that includes nine members: Src, Yes, Fyn, and Fgr, forming the SrcA subfamily, Lck, Hck, Blk, and Lyn in the SrcB subfamily, and Frk in its own subfamily. Frk has homologs in invertebrates such as flies and worms, and Src homologs exist in organisms as diverse as unicellular choanoflagellates, but the SrcA and SrcB subfamilies are specific to vertebrates. Src family kinases contain six conserved domains: a N-terminal myristoylated segment, a SH2 domain, a SH3 domain, a linker region, a tyrosine kinase domain, and C-terminal tail.

The insulin transduction pathway is a biochemical pathway by which insulin increases the uptake of glucose into fat and muscle cells and reduces the synthesis of glucose in the liver and hence is involved in maintaining glucose homeostasis. This pathway is also influenced by fed versus fasting states, stress levels, and a variety of other hormones.

<span class="mw-page-title-main">Autophosphorylation</span>

Autophosphorylation is a type of post-translational modification of proteins. It is generally defined as the phosphorylation of the kinase by itself. In eukaryotes, this process occurs by the addition of a phosphate group to serine, threonine or tyrosine residues within protein kinases, normally to regulate the catalytic activity. Autophosphorylation may occur when a kinases' own active site catalyzes the phosphorylation reaction, or when another kinase of the same type provides the active site that carries out the chemistry. The latter often occurs when kinase molecules dimerize. In general, the phosphate groups introduced are gamma phosphates from nucleoside triphosphates, most commonly ATP.

<span class="mw-page-title-main">Tyrosine phosphorylation</span> Phosphorylation of peptidyl-tyrosine

Tyrosine phosphorylation is the addition of a phosphate (PO43−) group to the amino acid tyrosine on a protein. It is one of the main types of protein phosphorylation. This transfer is made possible through enzymes called tyrosine kinases. Tyrosine phosphorylation is a key step in signal transduction and the regulation of enzymatic activity.

Non-catalytic tyrosine-phosphorylated receptors (NTRs), also called immunoreceptors or Src-family kinase-dependent receptors, are a group of cell surface receptors expressed by leukocytes that are important for cell migration and the recognition of abnormal cells or structures and the initiation of an immune response. These transmembrane receptors are not grouped into the NTR family based on sequence homology, but because they share a conserved signalling pathway utilizing the same signalling motifs. A signaling cascade is initiated when the receptors bind their respective ligand resulting in cell activation. For that tyrosine residues in the cytoplasmic tail of the receptors have to be phosphorylated, hence the receptors are referred to as tyrosine-phosphorylated receptors. They are called non-catalytic receptors, as the receptors have no intrinsic tyrosine kinase activity and cannot phosphorylate their own tyrosine residues. Phosphorylation is mediated by additionally recruited kinases. A prominent member of this receptor family is the T-cell receptor.

References

  1. 1 2 3 GRCh38: Ensembl release 89: ENSG00000171105 – Ensembl, May 2017
  2. 1 2 3 GRCm38: Ensembl release 89: ENSMUSG00000005534 – Ensembl, May 2017
  3. ↑ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  4. ↑ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  5. 1 2 3 Ward CW, Lawrence MC (April 2009). "Ligand-induced activation of the insulin receptor: a multi-step process involving structural changes in both the ligand and the receptor". BioEssays. 31 (4): 422–34. doi:10.1002/bies.200800210. PMID   19274663. S2CID   27645596.
  6. ↑ Ebina Y, Ellis L, Jarnagin K, Edery M, Graf L, Clauser E, Ou JH, Masiarz F, Kan YW, Goldfine ID (April 1985). "The human insulin receptor cDNA: the structural basis for hormone-activated transmembrane signalling". Cell. 40 (4): 747–58. doi:10.1016/0092-8674(85)90334-4. PMID   2859121. S2CID   23230348.
  7. ↑ Malaguarnera R, Sacco A, Voci C, Pandini G, Vigneri R, Belfiore A (May 2012). "Proinsulin binds with high affinity the insulin receptor isoform A and predominantly activates the mitogenic pathway". Endocrinology. 153 (5): 2152–63. doi: 10.1210/en.2011-1843 . PMID   22355074.
  8. 1 2 Belfiore A, Frasca F, Pandini G, Sciacca L, Vigneri R (October 2009). "Insulin receptor isoforms and insulin receptor/insulin-like growth factor receptor hybrids in physiology and disease". Endocrine Reviews. 30 (6): 586–623. doi: 10.1210/er.2008-0047 . PMID   19752219.
  9. ↑ Knudsen L, De Meyts P, Kiselyov VV (December 2011). "Insight into the molecular basis for the kinetic differences between the two insulin receptor isoforms" (PDF). The Biochemical Journal. 440 (3): 397–403. doi:10.1042/BJ20110550. PMID   21838706.
  10. 1 2 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 (April 2010). "Structural resolution of a tandem hormone-binding element in the insulin receptor and its implications for design of peptide agonists". Proceedings of the National Academy of Sciences of the United States of America. 107 (15): 6771–6. Bibcode:2010PNAS..107.6771S. doi: 10.1073/pnas.1001813107 . PMC   2872410 . PMID   20348418.
  11. ↑ McKern NM, Lawrence MC, Streltsov VA, Lou MZ, Adams TE, Lovrecz GO, Elleman TC, Richards KM, Bentley JD, Pilling PA, Hoyne PA, Cartledge KA, Pham TM, Lewis JL, Sankovich SE, Stoichevska V, Da Silva E, Robinson CP, Frenkel MJ, Sparrow LG, Fernley RT, Epa VC, Ward CW (September 2006). "Structure of the insulin receptor ectodomain reveals a folded-over conformation". Nature. 443 (7108): 218–21. Bibcode:2006Natur.443..218M. doi:10.1038/nature05106. PMID   16957736. S2CID   4381431.
  12. 1 2 Gutmann T, Kim KH, Grzybek M, Walz T, Coskun Ü (May 2018). "Visualization of ligand-induced transmembrane signaling in the full-length human insulin receptor". The Journal of Cell Biology. 217 (5): 1643–1649. doi:10.1083/jcb.201711047. PMC   5940312 . PMID   29453311.
  13. 1 2 Gutmann T, Schäfer IB, Poojari C, Brankatschk B, Vattulainen I, Strauss M, Coskun Ü (January 2020). "Cryo-EM structure of the complete and ligand-saturated insulin receptor ectodomain". The Journal of Cell Biology. 219 (1). doi: 10.1083/jcb.201907210 . PMC   7039211 . PMID   31727777.
  14. 1 2 3 Kiselyov VV, Versteyhe S, Gauguin L, De Meyts P (February 2009). "Harmonic oscillator model of the insulin and IGF1 receptors' allosteric binding and activation". Molecular Systems Biology. 5 (5): 243. doi:10.1038/msb.2008.78. PMC   2657531 . PMID   19225456.
  15. 1 2 de Meyts P, Roth J, Neville DM, Gavin JR, Lesniak MA (November 1973). "Insulin interactions with its receptors: experimental evidence for negative cooperativity". Biochemical and Biophysical Research Communications. 55 (1): 154–61. doi:10.1016/S0006-291X(73)80072-5. PMID   4361269.
  16. ↑ Kumar L, Vizgaudis W, Klein-Seetharaman J (July 2022). "Structure-based survey of ligand binding in the human insulin receptor". Br J Pharmacol. 179 (14): 3512–3528. doi: 10.1111/bph.15777 . PMID   34907529. S2CID   245242018.
  17. ↑ Berg JM, Tymoczko J, Stryer L, Berg JM, Tymoczko JL, Stryer L (2002). Biochemistry (5th ed.). W H Freeman. ISBN   0716730510.
  18. ↑ Duckworth WC, Bennett RG, Hamel FG (October 1998). "Insulin degradation: progress and potential". Endocrine Reviews. 19 (5): 608–24. doi: 10.1210/edrv.19.5.0349 . PMID   9793760.
  19. ↑ Tsai S, Clemente-Casares X, Zhou AC, Lei H, Ahn JJ, Chan YT, et al. (August 2018). "Insulin Receptor-Mediated Stimulation Boosts T Cell Immunity during Inflammation and Infection". Cell Metabolism. 28 (6): 922–934.e4. doi: 10.1016/j.cmet.2018.08.003 . PMID   30174303.
  20. ↑ Fischer HJ, Sie C, Schumann E, Witte AK, Dressel R, van den Brandt J, Reichardt HM (March 2017). "The Insulin Receptor Plays a Critical Role in T Cell Function and Adaptive Immunity". Journal of Immunology. 198 (5): 1910–1920. doi: 10.4049/jimmunol.1601011 . PMID   28115529.
  21. ↑ Longo N, Wang Y, Smith SA, Langley SD, DiMeglio LA, Giannella-Neto D (June 2002). "Genotype-phenotype correlation in inherited severe insulin resistance". Human Molecular Genetics. 11 (12): 1465–75. doi: 10.1093/hmg/11.12.1465 . PMID   12023989. S2CID   15924838.
  22. ↑ Melvin A, Stears A (2017). "Severe insulin resistance: pathologies". Practical Diabetes. 34 (6): 189–194a. doi: 10.1002/pdi.2116 . S2CID   90238599 . Retrieved 31 October 2020.
  23. ↑ Maddux BA, Goldfine ID (January 2000). "Membrane glycoprotein PC-1 inhibition of insulin receptor function occurs via direct interaction with the receptor alpha-subunit". Diabetes. 49 (1): 13–9. doi: 10.2337/diabetes.49.1.13 . PMID   10615944.
  24. ↑ Langlais P, Dong LQ, Hu D, Liu F (June 2000). "Identification of Grb10 as a direct substrate for members of the Src tyrosine kinase family". Oncogene. 19 (25): 2895–903. doi:10.1038/sj.onc.1203616. PMID   10871840. S2CID   25923169.
  25. ↑ Hansen H, Svensson U, Zhu J, Laviola L, Giorgino F, Wolf G, Smith RJ, Riedel H (April 1996). "Interaction between the Grb10 SH2 domain and the insulin receptor carboxyl terminus". The Journal of Biological Chemistry. 271 (15): 8882–6. doi: 10.1074/jbc.271.15.8882 . PMID   8621530.
  26. ↑ Liu F, Roth RA (October 1995). "Grb-IR: a SH2-domain-containing protein that binds to the insulin receptor and inhibits its function". Proceedings of the National Academy of Sciences of the United States of America. 92 (22): 10287–91. Bibcode:1995PNAS...9210287L. doi: 10.1073/pnas.92.22.10287 . PMC   40781 . PMID   7479769.
  27. ↑ He W, Rose DW, Olefsky JM, Gustafson TA (March 1998). "Grb10 interacts differentially with the insulin receptor, insulin-like growth factor I receptor, and epidermal growth factor receptor via the Grb10 Src homology 2 (SH2) domain and a second novel domain located between the pleckstrin homology and SH2 domains". The Journal of Biological Chemistry. 273 (12): 6860–7. doi: 10.1074/jbc.273.12.6860 . PMID   9506989.
  28. ↑ Frantz JD, Giorgetti-Peraldi S, Ottinger EA, Shoelson SE (January 1997). "Human GRB-IRbeta/GRB10. Splice variants of an insulin and growth factor receptor-binding protein with PH and SH2 domains". The Journal of Biological Chemistry. 272 (5): 2659–67. doi: 10.1074/jbc.272.5.2659 . PMID   9006901.
  29. ↑ Kasus-Jacobi A, Béréziat V, Perdereau D, Girard J, Burnol AF (April 2000). "Evidence for an interaction between the insulin receptor and Grb7. A role for two of its binding domains, PIR and SH2". Oncogene. 19 (16): 2052–9. doi:10.1038/sj.onc.1203469. PMID   10803466. S2CID   10955124.
  30. ↑ Aguirre V, Werner ED, Giraud J, Lee YH, Shoelson SE, White MF (January 2002). "Phosphorylation of Ser307 in insulin receptor substrate-1 blocks interactions with the insulin receptor and inhibits insulin action". The Journal of Biological Chemistry. 277 (2): 1531–7. doi: 10.1074/jbc.M101521200 . PMID   11606564.
  31. ↑ Sawka-Verhelle D, Tartare-Deckert S, White MF, Van Obberghen E (March 1996). "Insulin receptor substrate-2 binds to the insulin receptor through its phosphotyrosine-binding domain and through a newly identified domain comprising amino acids 591-786". The Journal of Biological Chemistry. 271 (11): 5980–3. doi: 10.1074/jbc.271.11.5980 . PMID   8626379.
  32. ↑ O'Neill TJ, Zhu Y, Gustafson TA (April 1997). "Interaction of MAD2 with the carboxyl terminus of the insulin receptor but not with the IGFIR. Evidence for release from the insulin receptor after activation". The Journal of Biological Chemistry. 272 (15): 10035–40. doi: 10.1074/jbc.272.15.10035 . PMID   9092546.
  33. ↑ Braiman L, Alt A, Kuroki T, Ohba M, Bak A, Tennenbaum T, Sampson SR (April 2001). "Insulin induces specific interaction between insulin receptor and protein kinase C delta in primary cultured skeletal muscle". Molecular Endocrinology. 15 (4): 565–74. doi: 10.1210/mend.15.4.0612 . PMID   11266508.
  34. ↑ Rosenzweig T, Braiman L, Bak A, Alt A, Kuroki T, Sampson SR (June 2002). "Differential effects of tumor necrosis factor-alpha on protein kinase C isoforms alpha and delta mediate inhibition of insulin receptor signaling". Diabetes. 51 (6): 1921–30. doi: 10.2337/diabetes.51.6.1921 . PMID   12031982.
  35. ↑ Maegawa H, Ugi S, Adachi M, Hinoda Y, Kikkawa R, Yachi A, Shigeta Y, Kashiwagi A (March 1994). "Insulin receptor kinase phosphorylates protein tyrosine phosphatase containing Src homology 2 regions and modulates its PTPase activity in vitro". Biochemical and Biophysical Research Communications. 199 (2): 780–5. doi:10.1006/bbrc.1994.1297. PMID   8135823.
  36. ↑ Kharitonenkov A, Schnekenburger J, Chen Z, Knyazev P, Ali S, Zwick E, White M, Ullrich A (December 1995). "Adapter function of protein-tyrosine phosphatase 1D in insulin receptor/insulin receptor substrate-1 interaction". The Journal of Biological Chemistry. 270 (49): 29189–93. doi: 10.1074/jbc.270.49.29189 . PMID   7493946.
  37. ↑ Kotani K, Wilden P, Pillay TS (October 1998). "SH2-Balpha is an insulin-receptor adapter protein and substrate that interacts with the activation loop of the insulin-receptor kinase". The Biochemical Journal. 335 (1): 103–9. doi:10.1042/bj3350103. PMC   1219757 . PMID   9742218.
  38. ↑ Nelms K, O'Neill TJ, Li S, Hubbard SR, Gustafson TA, Paul WE (December 1999). "Alternative splicing, gene localization, and binding of SH2-B to the insulin receptor kinase domain". Mammalian Genome. 10 (12): 1160–7. doi:10.1007/s003359901183. PMID   10594240. S2CID   21060861.

Further reading

This page is based on this Wikipedia article
Text is available under the CC BY-SA 4.0 license; additional terms may apply.
Images, videos and audio are available under their respective licenses.