Forum for Science, Industry and Business

Sponsored by:     3M 
Search our Site:

 

How the insulin receptor works

19.02.2018

As we are approaching the 100th anniversary of the discovery of insulin, a wide array of its signaling pathways has been defined. However, the initial step in insulin action, i.e. the engagement with its cell-surface receptor and the resulting conformational change, which propagates across the plasma membrane to the intracellular module, remains poorly understood. Addressing this problem, researchers from the Paul Langerhans Institute Dresden of the Helmholtz Zentrum München at the University Hospital Carl Gustav Carus of TU Dresden together with colleagues from Rockefeller University New York succeeded for the first time in the visualization of the insulin receptor activation.

Insulin exerts multiple effects on cellular metabolism and growth. The biological actions of insulin are mediated by a cell-surface receptor, called insulin receptor, which is present on the surface, i.e. the plasma membrane, of virtually all mammalian cells. The dysfunction of insulin receptor has been linked to severe pathologies including diabetes mellitus or cancer.


How the insulin receptor works

© Gutmann et al. 2018

Insulin binds outside the cell to the extracellular domain of its receptor and induces a structural change that is propagated across the membrane to the intracellular kinase domains inside the cell, causing them to activate each other, thus initiating signaling cascades. The nature of this structural change remained a mystery for decades, resulting in mutually exclusive models for insulin receptor activation being put forward.

“To obtain insights into receptor activation, we purified full-length insulin receptors and embedded them into nanodiscs, which are, as their name suggests, nanoscale disc-shaped membrane patches. Those could then be directly visualized by single-particle electron microscopy,” explains Theresia Gutmann, PhD student and co-first author of the study. She works at the Institute for Pancreatic Islet Research/Paul Langerhans Institute Dresden (IPI/PLID) which is run by Helmholtz Zentrum München together with the University Hospital Carl Gustav Carus of Technical University Dresden.

“This technology enables us to directly study the cell-surface receptors in an artificial membrane environment”, explains Dr. Ünal Coskun, group leader at IPI/PLID and co-senior author of the study. “In the absence of insulin, the receptor displays an inverted U-shaped ectodomain, which is consistent with previous crystallographic studies of isolated ectodomains, implying that the membrane-passing transmembrane domains and thus kinase domains are held well apart from each other.”

“Upon insulin binding, the ectodomain of the receptor undergoes a dramatic reorganization, changing from a U-shaped to a T-shaped structure and also causing a rearrangement of the transmembrane domains. These now come together likely facilitating kinase domain interactions and thus their activation”, Dr. Thomas Walz, professor at the Rockefeller University, continues.

Dr. Coskun summarizes: “These nanodisc-embedded receptors provide a novel platform to address further questions regarding insulin receptor regulation and eventually to test therapeutic agents.” “Our results directly demonstrate the structural transition in the full-length receptor upon insulin binding and offer an answer to the longstanding question concerning the mechanism by which insulin activates its receptor, thus improving our understanding of the receptor,” concludes Gutmann. The authors from Dresden are scientists in the German Center for Diabetes Research (DZD). The results of this collaborative work have now been published in the ‘Journal of Cell Biology’.

Further Information

Original Publication:
Gutmann, Kim et al. (2018): Visualization of ligand-induced transmembrane signaling in the full-length human insulin receptor. Journal of Cell Biology, DOI: 10.1083/jcb.201711047

The Helmholtz Zentrum München, the German Research Center for Environmental Health, pursues the goal of developing personalized medical approaches for the prevention and therapy of major common diseases such as diabetes and lung diseases. To achieve this, it investigates the interaction of genetics, environmental factors and lifestyle. The Helmholtz Zentrum München is headquartered in Neuherberg in the north of Munich and has about 2,300 staff members. It is a member of the Helmholtz Association, a community of 18 scientific-technical and medical-biological research centers with a total of about 37,000 staff members. http://www.helmholtz-muenchen.de/en

The Institute for Pancreatic Islet Researcht (IPI) focuses on basic and clinical research on pancreatic beta cells, which are responsible for production and secretion of insulin. http://www.helmholtz-muenchen.de/en/ipi

The German Center for Diabetes Research (DZD) is a national association that brings together experts in the field of diabetes research and combines basic research, translational research, epidemiology and clinical applications. The aim is to develop novel strategies for personalized prevention and treatment of diabetes. Members are Helmholtz Zentrum München – German Research Center for Environmental Health, the German Diabetes Center in Düsseldorf, the German Institute of Human Nutrition in Potsdam-Rehbrücke, the Paul Langerhans Institute Dresden of the Helmholtz Zentrum München at the University Medical Center Carl Gustav Carus of the TU Dresden and the Institute for Diabetes Research and Metabolic Diseases of the Helmholtz Zentrum München at the Eberhard-Karls-University of Tuebingen together with associated partners at the Universities in Heidelberg, Cologne, Leipzig, Lübeck and Munich. http://www.dzd-ev.de/en/index.html

Contact for the media:
Department of Communication, Helmholtz Zentrum München - German Research Center for Environmental Health, Ingolstädter Landstr. 1, 85764 Neuherberg - Tel. +49 89 3187 2238 - Fax: +49 89 3187 3324 - E-mail: presse@helmholtz-muenchen.de

Scientific Contact at Helmholtz Zentrum München:
Dr. Ünal Coskun, Helmholtz Zentrum München - German Research Center for Environmental Health, Institute for Pancreatic Islet Research, Fetscherstrasse 74, 01307 Dresden - Tel. +49 351 796 5340 - E-mail: uenal.coskun@helmholtz-muenchen.de

Sonja Opitz | Helmholtz Zentrum München - Deutsches Forschungszentrum für Gesundheit und Umwelt

Further reports about: Diabetes Environmental Health Gesundheit Helmholtz receptor transmembrane

All articles from Life Sciences >>>

The most recent press releases about innovation >>>

Die letzten 5 Focus-News des innovations-reports im Überblick:

Im Focus: Storage & Transport of highly volatile Gases made safer & cheaper by the use of “Kinetic Trapping"

Augsburg chemists present a new technology for compressing, storing and transporting highly volatile gases in porous frameworks/New prospects for gas-powered vehicles

Storage of highly volatile gases has always been a major technological challenge, not least for use in the automotive sector, for, for example, methane or...

Im Focus: Disrupting crystalline order to restore superfluidity

When we put water in a freezer, water molecules crystallize and form ice. This change from one phase of matter to another is called a phase transition. While this transition, and countless others that occur in nature, typically takes place at the same fixed conditions, such as the freezing point, one can ask how it can be influenced in a controlled way.

We are all familiar with such control of the freezing transition, as it is an essential ingredient in the art of making a sorbet or a slushy. To make a cold...

Im Focus: Micro energy harvesters for the Internet of Things

Fraunhofer IWS Dresden scientists print electronic layers with polymer ink

Thin organic layers provide machines and equipment with new functions. They enable, for example, tiny energy recuperators. In future, these will be installed...

Im Focus: Dynamik einzelner Proteine

Neue Messmethode erlaubt es Forschenden, die Bewegung von Molekülen lange und genau zu verfolgen

Das Zusammenspiel aus Struktur und Dynamik bestimmt die Funktion von Proteinen, den molekularen Werkzeugen der Zelle. Durch Fortschritte in der...

Im Focus: Dynamics of individual proteins

New measurement method allows researchers to precisely follow the movement of individual molecules over long periods of time

The function of proteins – the molecular tools of the cell – is governed by the interplay of their structure and dynamics. Advances in electron microscopy have...

All Focus news of the innovation-report >>>

Anzeige

Anzeige

VideoLinks
Industry & Economy
Event News

5th International Conference on Cellular Materials (CellMAT), Scientific Programme online

02.10.2018 | Event News

Major Project: The New Silk Road

01.10.2018 | Event News

"Boston calling": TU Berlin and the Weizenbaum Institute organize a conference in USA

21.09.2018 | Event News

 
Latest News

Physics: Not everything is where it seems to be

15.10.2018 | Physics and Astronomy

Microfluidic molecular exchanger helps control therapeutic cell manufacturing

15.10.2018 | Life Sciences

Link between Gut Flora and Multiple Sclerosis Discovered

15.10.2018 | Life Sciences

VideoLinks
Science & Research
Overview of more VideoLinks >>>