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The Ephb2 Receptor Uses Homotypic, Head-to-Tail Interactions within Its Ectodomain as an Autoinhibitory Control Mechanism

The Eph receptor tyrosine kinases and their ephrin ligands direct axon pathfinding and neuronal cell migration, as well as mediate many other cell–cell communication events. Their dysfunctional signaling has been shown to lead to various diseases, including cancer. The Ephs and ephrins both localize...

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Autores principales: Xu, Yan, Robev, Dorothea, Saha, Nayanendu, Wang, Bingcheng, Dalva, Matthew B., Xu, Kai, Himanen, Juha P., Nikolov, Dimitar B.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8508685/
https://www.ncbi.nlm.nih.gov/pubmed/34638814
http://dx.doi.org/10.3390/ijms221910473
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author Xu, Yan
Robev, Dorothea
Saha, Nayanendu
Wang, Bingcheng
Dalva, Matthew B.
Xu, Kai
Himanen, Juha P.
Nikolov, Dimitar B.
author_facet Xu, Yan
Robev, Dorothea
Saha, Nayanendu
Wang, Bingcheng
Dalva, Matthew B.
Xu, Kai
Himanen, Juha P.
Nikolov, Dimitar B.
author_sort Xu, Yan
collection PubMed
description The Eph receptor tyrosine kinases and their ephrin ligands direct axon pathfinding and neuronal cell migration, as well as mediate many other cell–cell communication events. Their dysfunctional signaling has been shown to lead to various diseases, including cancer. The Ephs and ephrins both localize to the plasma membrane and, upon cell–cell contact, form extensive signaling assemblies at the contact sites. The Ephs and the ephrins are divided into A and B subclasses based on their sequence conservation and affinities for each other. The molecular details of Eph–ephrin recognition have been previously revealed and it has been documented that ephrin binding induces higher-order Eph assemblies, which are essential for full biological activity, via multiple, distinct Eph–Eph interfaces. One Eph–Eph interface type is characterized by a homotypic, head-to-tail interaction between the ligand-binding and the fibronectin domains of two adjacent Eph molecules. While the previous Eph ectodomain structural studies were focused on A class receptors, we now report the crystal structure of the full ectodomain of EphB2, revealing distinct and unique head-to-tail receptor–receptor interactions. The EphB2 structure and structure-based mutagenesis document that EphB2 uses the head-to-tail interactions as a novel autoinhibitory control mechanism for regulating downstream signaling and that these interactions can be modulated by posttranslational modifications.
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spelling pubmed-85086852021-10-13 The Ephb2 Receptor Uses Homotypic, Head-to-Tail Interactions within Its Ectodomain as an Autoinhibitory Control Mechanism Xu, Yan Robev, Dorothea Saha, Nayanendu Wang, Bingcheng Dalva, Matthew B. Xu, Kai Himanen, Juha P. Nikolov, Dimitar B. Int J Mol Sci Article The Eph receptor tyrosine kinases and their ephrin ligands direct axon pathfinding and neuronal cell migration, as well as mediate many other cell–cell communication events. Their dysfunctional signaling has been shown to lead to various diseases, including cancer. The Ephs and ephrins both localize to the plasma membrane and, upon cell–cell contact, form extensive signaling assemblies at the contact sites. The Ephs and the ephrins are divided into A and B subclasses based on their sequence conservation and affinities for each other. The molecular details of Eph–ephrin recognition have been previously revealed and it has been documented that ephrin binding induces higher-order Eph assemblies, which are essential for full biological activity, via multiple, distinct Eph–Eph interfaces. One Eph–Eph interface type is characterized by a homotypic, head-to-tail interaction between the ligand-binding and the fibronectin domains of two adjacent Eph molecules. While the previous Eph ectodomain structural studies were focused on A class receptors, we now report the crystal structure of the full ectodomain of EphB2, revealing distinct and unique head-to-tail receptor–receptor interactions. The EphB2 structure and structure-based mutagenesis document that EphB2 uses the head-to-tail interactions as a novel autoinhibitory control mechanism for regulating downstream signaling and that these interactions can be modulated by posttranslational modifications. MDPI 2021-09-28 /pmc/articles/PMC8508685/ /pubmed/34638814 http://dx.doi.org/10.3390/ijms221910473 Text en © 2021 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Xu, Yan
Robev, Dorothea
Saha, Nayanendu
Wang, Bingcheng
Dalva, Matthew B.
Xu, Kai
Himanen, Juha P.
Nikolov, Dimitar B.
The Ephb2 Receptor Uses Homotypic, Head-to-Tail Interactions within Its Ectodomain as an Autoinhibitory Control Mechanism
title The Ephb2 Receptor Uses Homotypic, Head-to-Tail Interactions within Its Ectodomain as an Autoinhibitory Control Mechanism
title_full The Ephb2 Receptor Uses Homotypic, Head-to-Tail Interactions within Its Ectodomain as an Autoinhibitory Control Mechanism
title_fullStr The Ephb2 Receptor Uses Homotypic, Head-to-Tail Interactions within Its Ectodomain as an Autoinhibitory Control Mechanism
title_full_unstemmed The Ephb2 Receptor Uses Homotypic, Head-to-Tail Interactions within Its Ectodomain as an Autoinhibitory Control Mechanism
title_short The Ephb2 Receptor Uses Homotypic, Head-to-Tail Interactions within Its Ectodomain as an Autoinhibitory Control Mechanism
title_sort ephb2 receptor uses homotypic, head-to-tail interactions within its ectodomain as an autoinhibitory control mechanism
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8508685/
https://www.ncbi.nlm.nih.gov/pubmed/34638814
http://dx.doi.org/10.3390/ijms221910473
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