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.

doi:10.3390/ijms221910473

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

Journal Article · Tue Sep 28 00:00:00 EDT 2021 · International Journal of Molecular Sciences (Online)

DOI:https://doi.org/10.3390/ijms221910473· OSTI ID:1829867

Xu, Yan ^[1]; Robev, Dorothea ^[2]; Saha, Nayanendu ^[2]; Wang, Bingcheng ^[3]; Dalva, Matthew B. ^[4]; Xu, Kai ^[1]; ^[2]; Nikolov, Dimitar B. ^[2]

The Ohio State Univ., Columbus, OH (United States). Dept. of Veterinary Biosciences. College of Veterinary Medicine; Memorial Sloan-Kettering Cancer Center, New York, NY (United States). Structural Biology Program
Memorial Sloan-Kettering Cancer Center, New York, NY (United States). Structural Biology Program
MetroHealth Medical Center, Cleveland, OH (United States). Rammelkamp Center for Research
Thomas Jefferson Univ., Philadelphia, PA (United States). Dept. of Neuroscience. Jefferson Center for Synaptic Biology

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.

View Accepted Manuscript (DOE)

Research Organization:: Argonne National Laboratory (ANL), Argonne, IL (United States). Advanced Photon Source (APS)

Sponsoring Organization:: USDOE Office of Science (SC)

OSTI ID:: 1829867

Journal Information:: International Journal of Molecular Sciences (Online), Journal Name: International Journal of Molecular Sciences (Online) Journal Issue: 19 Vol. 22; ISSN 1422-0067

Publisher:: MDPICopyright Statement

Country of Publication:: United States

Language:: ENGLISH

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

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