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Molecular Architecture of a Network of Potential Intracellular EGFR Modulators Involving the Juxtamembrane Segment, ARNO, Phospholipids and CaM

25 Pages Posted: 26 Aug 2019 Publication Status: Published

See all articles by Aldino Viegas

Aldino Viegas

Heinrich Heine University Dusseldorf - Institute of Physical Biology

Dongsheng M. Yin

Center of Advanced European Studies and Research, Germany (CAESAR) - Max Planck Fellow Chemical Biology

Jan Borggräfe

Heinrich Heine University Dusseldorf - Institute of Physical Biology

Thibault Viennet

Heinrich Heine University Dusseldorf - Institute of Physical Biology

Marcel Falke

Heinrich Heine University Dusseldorf - Institute of Physical Biology

Anton Schmitz

Center of Advanced European Studies and Research, Germany (CAESAR) - Max Planck Fellow Chemical Biology; University of Bonn - Department of Chemical Biology

Michael Famulok

Center of Advanced European Studies and Research, Germany (CAESAR) - Max Planck Fellow Chemical Biology

Manuel Etzkorn

Heinrich Heine University Dusseldorf - Institute of Physical Biology; Forschungszentrum Jülich GmbH - Institute of Complex Systems (ICS-6); Forschungszentrum Jülich GmbH - JuStruct: Jülich Center for Structural Biology

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Abstract

Signaling of the Epidermal growth factor receptors (EGFRs) is a central cellular element and its dysregulation is related to a number of severe diseases. While ligand binding to the extracellular domain is the receptor’s most obvious regulatory element, also intracellular factors can act as modulators of EGFR activity. The juxtamembrane (JM) segment of the EGFR seems to be a key interaction interface of these cytoplasmic factors. However, very few JM-interacting molecules have been identified so far and even fewer is known about the molecular mechanism underlying JM-targeted receptor modulation. Here we report ARNO as a new EGFR-JM binding protein and provide high-resolution insights into its mode of interaction. We obtain comparable insights also for the known interaction partners Calmodulin and phospholipid bilayers containing different lipid compositions. Our results show clear similarities and distinct differences in each binding mode. Furthermore, we show that each interaction can be modulated by a set of additional orthogonal factors generating a distinctly regulated competitive network of possible EGFR modulators acting on the intracellular domain of the receptor. This newly identified interaction network and the obtained insights into the underlaying molecular mechanism may foster future EGFR-targeted therapeutic strategies.

Keywords: EGFR, Juxtamembrane, ARNO-Sec7, Cytohesins, NMR

Suggested Citation

Viegas, Aldino and Yin, Dongsheng M. and Borggräfe, Jan and Viennet, Thibault and Falke, Marcel and Schmitz, Anton and Famulok, Michael and Etzkorn, Manuel, Molecular Architecture of a Network of Potential Intracellular EGFR Modulators Involving the Juxtamembrane Segment, ARNO, Phospholipids and CaM (August 23, 2019). Available at SSRN: https://ssrn.com/abstract=3441425 or http://dx.doi.org/10.2139/ssrn.3441425
This is a paper under consideration at Cell Press and has not been peer-reviewed.

Aldino Viegas

Heinrich Heine University Dusseldorf - Institute of Physical Biology

Düsseldorf, 40225
Germany

Dongsheng M. Yin

Center of Advanced European Studies and Research, Germany (CAESAR) - Max Planck Fellow Chemical Biology

Ludwig-Erhard-Allee 2
Bonn
Germany

Jan Borggräfe

Heinrich Heine University Dusseldorf - Institute of Physical Biology

Düsseldorf, 40225
Germany

Thibault Viennet

Heinrich Heine University Dusseldorf - Institute of Physical Biology

Düsseldorf, 40225
Germany

Marcel Falke

Heinrich Heine University Dusseldorf - Institute of Physical Biology

Düsseldorf, 40225
Germany

Anton Schmitz

Center of Advanced European Studies and Research, Germany (CAESAR) - Max Planck Fellow Chemical Biology ( email )

Ludwig-Erhard-Allee 2
Bonn
Germany

University of Bonn - Department of Chemical Biology ( email )

Gerhard-Domagk-Str.1
Bonn, 53121
Germany

Michael Famulok

Center of Advanced European Studies and Research, Germany (CAESAR) - Max Planck Fellow Chemical Biology

Ludwig-Erhard-Allee 2
Bonn
Germany

Manuel Etzkorn (Contact Author)

Heinrich Heine University Dusseldorf - Institute of Physical Biology ( email )

Düsseldorf, 40225
Germany

Forschungszentrum Jülich GmbH - Institute of Complex Systems (ICS-6) ( email )

Jülich, 52425
Germany

Forschungszentrum Jülich GmbH - JuStruct: Jülich Center for Structural Biology ( email )

Wilhelm Jonen Strasse
Jülich, 52425
Germany

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