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Domain structure of the human insulin receptor. L1, first leucine-rich repeat domain; CR, cysteine-rich region; L2, second leucine-rich repeat domain; FnIII-1, -2, -3, first, second, and third fibronectin type III domains; ID, insert domain; TM/JM, trans- and juxtamembrane regions; TK, tyrosine kinase domain. The second fibronectin Type III domain and the insert domain span both the α- and the β-chains of the mature protein. The critical C-terminal segment of the α-chain (αCT) is indicated by a red asterisk. Inter-chain and inter-monomer disulfide bonds are indicated by black line segments and membrane and cytoplasmic regions are shown in dashed outline.
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Ever since the discovery of insulin and its role in the regulation of glucose uptake and utilization, there has been great interest in insulin, its structure and the way in which it interacts with its receptor and effects signal transduction. As the 90th anniversary of the discovery of insulin approaches, it is timely to provide an overview of the...
Context in source publication
Context 1
... cDNA sequence for the human IR was determined indepen- dently by two laboratories in 1985 ( Ebina et al., 1985;Ullrich et al., 1985) and immediately revealed that there were two iso- forms of the receptor that differed by the absence (in the IR-A isoform) or presence (in the IR-B isoform) of an additional 12 residues between residues 716 and 717. These, and subsequent amino acid analyses (reviewed in Adams et al., 2000), revealed that each receptor monomer consists, from its N-terminus to C-terminus (Figure 3), of a leucine-rich repeat domain (L1), a cysteine-rich region (CR), a second leucine-rich repeat domain (L2), and three fibronectin type III domains (FnIII-1, FnIII-2, and FnIII-3), with FnIII-2 containing a large (∼120 residues) insert domain (ID). The ID contains the furin cleavage site that yields the α-chain and β-chain of the mature receptor monomer. ...
Citations
... Sanger has sequenced the amino acid sequence of insulin in 1971 (Stretton, 2002). The crystal structure of insulin was reported by Hodgkin (Blundell et al., 1971;Dodson et al., 1966;Harding et al., 1966;Howard, 2003;Ward & Lawrence, 2011). According to WHO, insulin belongs to the group of essential medicines (WHO, 2021). ...
Insulin was discovered 100 years ago and has been well studied from the perspectives of life and biomedical sciences. This paper reports chemical and biothermodynamic properties of biosynthesis of insulin. This paper reports for the first time the molecular and empirical formulas, biosynthesis reactions, and thermodynamic properties of molecules and their biosynthesis for human preproinsulin, proinsulin, insulin chain A, insulin chain B, insulin, signal peptide and intermediate peptide (C-peptide). Based on these, metabolic reactions were formulated for conversion of preproinsulin to insulin and their thermodynamic feasibility was analyzed.Communicated by Ramaswamy H. Sarma.
... The insulin superfamily of peptides, including insulin and insulinlike growth factors 1 and 2 (IGF1 and IGF2), plays essential roles in regulating cellular proliferation, differentiation, development, and metabolism in various tissues (1,2). Recent studies suggest that these peptides are also critical for the development and plasticity of the central nervous system (CNS) (3,4). ...
The insulin superfamily of peptides is essential for homeostasis as well as neuronal plasticity, learning, and memory. Here, we show that insulin-like growth factors 1 and 2 (IGF1 and IGF2) are differentially expressed in hippocampal neurons and released in an activity-dependent manner. Using a new fluorescence resonance energy transfer sensor for IGF1 receptor (IGF1R) with two-photon fluorescence lifetime imaging, we find that the release of IGF1 triggers rapid local autocrine IGF1R activation on the same spine and more than several micrometers along the stimulated dendrite, regulating the plasticity of the activated spine in CA1 pyramidal neurons. In CA3 neurons, IGF2, instead of IGF1, is responsible for IGF1R autocrine activation and synaptic plasticity. Thus, our study demonstrates the cell type-specific roles of IGF1 and IGF2 in hippocampal plasticity and a plasticity mechanism mediated by the synthesis and autocrine signaling of IGF peptides in pyramidal neurons.
... Insulin was the first peptide hormone discovered in 1922 during the examination of pancreatic extracts in diabetes research [9,10]. However, it took nearly two and a half decades to achieve the physicochemical characterization of insulin [11]. Finally, after determining the amino acid sequence of insulin using Sanger sequencing in 1955, it became clear that, as a heterodimer composed of 51 amino acids, the insulin molecule consists of two chains: a 21-residue A-chain linked to a 30-residue B chain by two disulfide bonds derived from cysteine residues (A7-B7 and A20-B19). ...
The comprehensive anabolic effects of insulin throughout the body, in addition to the control of glycemia, include ensuring lipid homeostasis and anti-inflammatory modulation, especially in adipose tissue (AT). The prevalence of obesity, defined as a body mass index (BMI) ≥ 30 kg/m2, has been increasing worldwide on a pandemic scale with accompanying syndemic health problems, including glucose intolerance, insulin resistance (IR), and diabetes. Impaired tissue sensitivity to insulin or IR paradoxically leads to diseases with an inflammatory component despite hyperinsulinemia. Therefore, an excess of visceral AT in obesity initiates chronic low-grade inflammatory conditions that interfere with insulin signaling via insulin receptors (INSRs). Moreover, in response to IR, hyperglycemia itself stimulates a primarily defensive inflammatory response associated with the subsequent release of numerous inflammatory cytokines and a real threat of organ function deterioration. In this review, all components of this vicious cycle are characterized with particular emphasis on the interplay between insulin signaling and both the innate and adaptive immune responses related to obesity. Increased visceral AT accumulation in obesity should be considered the main environmental factor responsible for the disruption in the epigenetic regulatory mechanisms in the immune system, resulting in autoimmunity and inflammation.
... The structure and function of Ilps are highly conserved in vertebrates and invertebrates. Ilps can regulate trehalose levels by changing the content of glucose, glycogen, and other sugars [11], while insulin receptor (InR), a receptor tyrosine kinase, binds with Ilps to activate a cascade reaction [12]. While most Hemiptera and Hymenoptera species have two InRs [13][14][15], a single InR is predominant in Diptera and Lepidoptera [16][17][18]. ...
Background
The nutritional signaling pathway regulates an insect’s size, development, and lifespan, as well as playing a vital role in reproduction. The insulin/insulin-like growth factor signaling (IIS) pathway plays a key role in the nutrition signaling pathway. As an integral component of the IIS pathway, insulin receptor (InR), a receptor tyrosine kinase, plays a role in the insulin pathway by controlling reproduction in many insect species. However, the precise molecular function of InR in non-model insect reproduction is poorly understood.Methods
In our study, Chilo suppressalis, a well-known rice pest, was used as a molecular system to determine the role of InR in insect reproduction. Sequencing the InR gene of C. suppressalis, comparing the amino acid sequence-specific structure, and constructing a phylogenetic tree revealed that this gene has four main domains: ligand binding L domain, Furin-like region, fibronectin type III domains, and Tyrosine kinase catalytic domain, which were all highly conserved in insects.ResultsBy characterizing the spatiotemporal expression profile of InR in different developmental stages and tissues, we found that InR gene expression was highest on the 3-day old in female pupae, 6th instar larvae, and fat body on the 6-day old in female pupae. InR gene expression may promote the molting and pupation of larvae and play a role in reproduction in the fat body. Furthermore, the RNA interference knockdown of InR dramatically reduced yolk deposition and blocked oocyte maturation. After suppression of InR, the expression of several other genes fluctuated to varying degrees.Conclusion
In conclusion, InR is vital to reproduction and is expected to become a new target for pest management.
... La purification de l'insuline ouvrit non seulement la porte à une des révolutions thérapeutiques les plus importantes du 20 e siècle, mais au cours des décennies suivantes a permis des avancées majeures en recherche fondamentale, notamment comme modèle pour l'étude des protéines, quoique à un rythme nettement plus lent que les retombées cliniques, dépendantes du développement de progrès technologiques Ward & Lawrence, 2011 ;Jörgens & Porta, 2020 ;Fralick & Zinman, 2021 ;White & Kahn, 2021). L'insuline fut cristallisée pour la première fois en 1926 par John Abel à Baltimore (Abel, 1926). ...
... Ceci clôture mes réminiscences des étapes qui conduisirent à la découverte du récepteur de l'insuline en 1970/71. Les étapes marquantes (choix nécessairement subjectif) qui conduiront après 1971 à l'avènement des études structurales du récepteur et de son complexe avec l'insuline sont résumées dans le tableau 1 (pour revue, voir aussi Freychet, 2002 ;De Meyts and Whittaker, 2002 ;Saltiel & Pessin, 2007 ;Ward & Lawrence, 2011 ;De Meyts & Lefèbvre, 2019 ;Kasuga, 2019 ;Flier & Kahn, 2021 ;White & Kahn, 2021). ...
... The binding of these peptides to their cognate receptors regulates key biological processes implicated in glucose homeostasis and cellular growth. [1][2][3][4][5][6][7][8][9][10][11][12] While Ins is a dual-chain (dc) peptide, consisting of an A-chain (21 residues) and a B-chain (30 residues) linked by three disulfide bonds, IGF1 is a single chain (sc) peptide with 70 residues, among which the residues 1-29, 30-41, 42-62, and 63-70 correspond to the B-, C-, A-, and D-domains, respectively. Ins modulates several physiological processes but is primarily responsible for maintaining the glucose level in blood. ...
The insulin receptor (IR), the insulin‐like growth factor‐1 receptor (IGF1R), and the insulin/IGF1 hybrid receptors (hybR) are homologous transmembrane receptors. The peptide ligands, insulin and IGF1, exhibit significant structural homology and can bind to each receptor via site‐1 and site‐2 residues with distinct affinities. The variants of the Iridoviridae virus family show capability in expressing single‐chain insulin/IGF1 like proteins, termed viral insulin‐like peptides (VILPs), which can stimulate receptors from the insulin family. The sequences of VILPs lacking the central C‐domain (dcVILPs) are known, but their structures in unbound and receptor‐bound states have not been resolved to date. We report all‐atom structural models of three dcVILPs (dcGIV, dcSGIV, and dcLCDV1) and their complexes with the receptors (μIR, μIGF1R, and μhybR), and probed the peptide/receptor interactions in each system using all‐atom molecular dynamics (MD) simulations. Based on the non‐bonded interaction energies computed between each residue of peptides (insulin and dcVILPs) and the receptors, we provide details on residues establishing significant interactions. The observed site‐1 insulin/μIR interactions are consistent with previous experimental studies, and a residue‐level comparison of interactions of peptides (insulin and dcVILPs) with the receptors revealed that due to sequence differences, dcVILPs also establish some interactions distinct from those between insulin and IR. We also designed insulin analogs and report enhanced interactions between some analogs and the receptors.
... La purification de l'insuline ouvrit non seulement la porte à une des révolutions thérapeutiques les plus importantes du 20 e siècle, mais au cours des décennies suivantes a permis des avancées majeures en recherche fondamentale, notamment comme modèle pour l'étude des protéines, quoique à un rythme nettement plus lent que les retombées cliniques, dépendantes du développement de progrès technologiques Ward & Lawrence, 2011 ;Jörgens & Porta, 2020 ;Fralick & Zinman, 2021 ;White & Kahn, 2021). L'insuline fut cristallisée pour la première fois en 1926 par John Abel à Baltimore (Abel, 1926). ...
... Ceci clôture mes réminiscences des étapes qui conduisirent à la découverte du récepteur de l'insuline en 1970/71. Les étapes marquantes (choix nécessairement subjectif) qui conduiront après 1971 à l'avènement des études structurales du récepteur et de son complexe avec l'insuline sont résumées dans le tableau 1 (pour revue, voir aussi Freychet, 2002 ;De Meyts and Whittaker, 2002 ;Saltiel & Pessin, 2007 ;Ward & Lawrence, 2011 ;De Meyts & Lefèbvre, 2019 ;Kasuga, 2019 ;Flier & Kahn, 2021 ;White & Kahn, 2021). ...
L’isolement de l’insuline du pancréas et sa purification à un degré suffisant pour permettre son administration à des patients atteints de diabète de type 1 furent accomplis il y a 100 ans à l’Université de Toronto par Banting, Best, Collip et McLeod et représentent sans conteste une des plus grandes révolutions thérapeutiques en médecine, reconnue par l’attribution du Prix Nobel de Physiologie ou Médecine en 1923 à Banting et McLeod. Les retombées cliniques furent rapides ainsi que l’internationalisation de sa production commerciale. Les retombées en matière de recherche fondamentale furent beaucoup plus lentes, en particulier en ce qui concerne les mécanismes moléculaires d’action de l’insuline sur ses cellules cibles. Presque un demi-siècle s’écoula avant la détermination de la structure tri-dimensionnelle de l’insuline en 1969 et la caractérisation de son récepteur cellulaire en 1970–1971. Le fait que le récepteur de l’insuline soit une enzyme appelée tyrosine kinase ne fut démontré que dans les années 1982–1985, et la structure cristallographique du domaine kinase intracellulaire fut déterminée dix ans plus tard. La structure cristallographique du premier substrat intracellulaire de la kinase (IRS-1) en 1991 ouvrira la voie à l’élucidation des voies de signalisation intracellulaires. Il faudra 15 ans de plus avant l’obtention de la structure cristallographique du domaine extracellulaire du récepteur (en l’absence d’insuline) en 2006. Depuis, la détermination de la structure du complexe insuline-récepteur dans les états inactif et activé a fait d’énormes progrès, en particulier grâce aux améliorations récentes dans les pouvoirs de résolution de la cryo-microscopie électronique. Je passerai ici en revue les étapes du développement du concept de récepteur hormonal, et de nos connaissances sur la structure et le mécanisme moléculaire d’activation du récepteur de l’insuline.
... Integrating these algorithms into the next generation of smart insulin pens may help reduce the burden on individuals and HCPs in terms of data interpretation and insulin dose calculations while also limiting costs [159]. However, despite the enormous potential of these more recent advances to improve diabetes care [160], current global access to insulin remains a significant concern in, but not exclusively, low-and middle-income countries [161]. While biosimilar insulins may help improve access to the drug itself, many of the barriers, such as cost and lack of human resources for training and education, will similarly impact on the potential progress with newer technologies. ...
The first preparation of insulin extracted from a pancreas and made suitable for use in humans after purification was achieved 100 years ago in Toronto, an epoch-making achievement, which has ultimately provided a life-giving treatment for millions of people worldwide. The earliest animal-derived formulations were short-acting and contained many impurities that caused adverse reactions, thereby limiting their therapeutic potential. However, since then, insulin production and purification improved with enhanced technologies, along with a full understanding of the insulin molecule structure. The availability of radio-immunoassays contributed to the unravelling of the physiology of glucose homeostasis, ultimately leading to the adoption of rational models of insulin replacement. The introduction of recombinant DNA technologies has since resulted in the era of both rapid- and long-acting human insulin analogues administered via the subcutaneous route which better mimic the physiology of insulin secretion, leading to the modern basal-bolus regimen. These advances, in combination with improved education and technologies for glucose monitoring, enable people with diabetes to better meet individual glycaemic goals with a lower risk of hypoglycaemia. While the prevalence of diabetes continues to rise globally, it is important to recognise the scientific endeavour that has led to insulin remaining the cornerstone of diabetes management, on the centenary of its first successful use in humans.
... The three fibronectin-III domains marked as FnIII-1, FnIII-2, and FnIII-3 contribute to the synthesis of C-terminals of the ectodomain of receptor. Each domain (FnIII-1 and FnIII-3) contains 100 amino acids, while domain FnIII-2 is composed of 120-amino acids [6]. ...
Global burden of type 2 diabetes mellitus is the main focus of the research studies in the world to understand fine details of normal metabolic and Mitogenic actions of insulin coupled with minute knowledge of the molecular causes of the insulin resistance and defect in the insulin signaling pathways that contribute to impaired carbohydrate metabolism in body. This review article provides thorough description of the insulin mediated signaling pathways and role of implicated effector molecules that are part of impaired signaling pathways to reach a consensus helpful in developing newer diagnostic as well as therapeutic molecules.
... Insulin was first identified and isolated by Drs. Fredrick Banting and Charles Best with the support of Professor John MacLeod and James Collip from the pancreatic extract of dogs (4)(5)(6)(7). Insulin was first used about 100 years ago to save a 14 year old boy who was suffering from type 1 diabetes mellitus (2). The discovery of animal-sourced insulin is one of the revolutionary breakthroughs in molecular medicine and it is also known as a 'miracle drug' (8). ...
... Though insulin is not the first protein to have its structure determined, it is capped as the first protein hormone whose three-dimensional structure in dimeric and hexameric forms was determined using X-ray crystallography at a high resolution (14). While the focus of this review article is on modeling and simulation studies, the research findings from experiments on the synthesis, structure, conformational changes, physiological applications, and interactions with the receptor are summarized in several published reviews (2,3,(5)(6)(7)(15)(16)(17)(18)(19)(20)(21)(22)(23)(24)(25)(26)(27)(28)(29). ...
Insulin is a peptide hormone known for chiefly regulating glucose level in blood among several other metabolic processes. Insulin remains the most effective drug for treating diabetes mellitus. Insulin is synthesized in the pancreatic β-cells where it exists in a compact hexameric architecture although its biologically active form is monomeric. Insulin exhibits a sequence of conformational variations during the transition from the hexamer state to its biologically-active monomer state. The structural transitions and the mechanism of action of insulin have been investigated using several experimental and computational methods. This review primarily highlights the contributions of molecular dynamics (MD) simulations in elucidating the atomic-level details of conformational dynamics in insulin, where the structure of the hormone has been probed as a monomer, dimer, and hexamer. The effect of solvent, pH, temperature, and pressure have been probed at the microscopic scale. Given the focus of this review on the structure of the hormone, simulation studies involving interactions between the hormone and its receptor are only briefly highlighted, and studies on other related peptides (e.g., insulin-like growth factors) are not discussed. However, the review highlights conformational dynamics underlying the activities of reported insulin analogs and mimetics. The future prospects for computational methods in developing promising synthetic insulin analogs are also briefly highlighted.
