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

TY - JOUR

T1 - Molecular Architecture of a Network of Potential Intracellular EGFR Modulators

T2 - ARNO, CaM, Phospholipids, and the Juxtamembrane Segment

AU - Viegas, Aldino

AU - Yin, Dongsheng M.

AU - Borggräfe, Jan

AU - Viennet, Thibault

AU - Falke, Marcel

AU - Schmitz, Anton

AU - Famulok, Michael

AU - Etzkorn, Manuel

N1 - Publisher Copyright: © 2019 Elsevier Ltd

PY - 2020/1/7

Y1 - 2020/1/7

N2 - Epidermal growth factor receptors (EGFRs) are central cellular signaling interfaces whose misregulation is related to several severe diseases. Although ligand binding to the extracellular domain is the most obvious regulatory element, also intracellular factors can act as modulators of EGFR activity. The juxtamembrane (JM) segment seems to be the receptor's key interaction interface of these cytoplasmic factors. However, only a limited number of cytoplasmic EGFR modulators are known and a comprehensive understanding of their mode of action is lacking. Here, we report ARNO, a member of the cytohesin family, as another JM-binding protein and structurally characterize the ARNO-EGFR interaction interface. We reveal that its binding mode displays common features and distinct differences with JM's interaction with calmodulin and anionic phospholipids. Furthermore, we show that each interaction can be modulated by additional factors, generating a distinctly regulated network of possible EGFR modulators acting on the intracellular domain of the receptor. Interactions with the intracellular juxtamembrane (JM) segment of the membrane spanning epidermal growth factor receptor (EGFR) can modulate its vital signaling. Viegas et al. unravel an interaction network comprising lipids, proteins, as well as individual cofactors, and characterize the molecular mechanisms of the respective interactions with EGFR's JM segment.

AB - Epidermal growth factor receptors (EGFRs) are central cellular signaling interfaces whose misregulation is related to several severe diseases. Although ligand binding to the extracellular domain is the most obvious regulatory element, also intracellular factors can act as modulators of EGFR activity. The juxtamembrane (JM) segment seems to be the receptor's key interaction interface of these cytoplasmic factors. However, only a limited number of cytoplasmic EGFR modulators are known and a comprehensive understanding of their mode of action is lacking. Here, we report ARNO, a member of the cytohesin family, as another JM-binding protein and structurally characterize the ARNO-EGFR interaction interface. We reveal that its binding mode displays common features and distinct differences with JM's interaction with calmodulin and anionic phospholipids. Furthermore, we show that each interaction can be modulated by additional factors, generating a distinctly regulated network of possible EGFR modulators acting on the intracellular domain of the receptor. Interactions with the intracellular juxtamembrane (JM) segment of the membrane spanning epidermal growth factor receptor (EGFR) can modulate its vital signaling. Viegas et al. unravel an interaction network comprising lipids, proteins, as well as individual cofactors, and characterize the molecular mechanisms of the respective interactions with EGFR's JM segment.

KW - ARNO-Sec7

KW - cytohesins

KW - EGFR

KW - juxtamembrane

KW - NMR

UR - http://www.scopus.com/inward/record.url?scp=85077761425&partnerID=8YFLogxK

U2 - 10.1016/j.str.2019.11.001

DO - 10.1016/j.str.2019.11.001

M3 - Journal article

C2 - 31780432

AN - SCOPUS:85077761425

SN - 0969-2126

VL - 28

SP - 54

EP - 62

JO - Structure

JF - Structure

IS - 1

ER -