Ternary Neurexin-T178-PTPR complexes represent a pre-synaptic core-module of neuronal synapse organization
11 affiliations
- 1Institute of Physiology, Faculty of Medicine, University of Freiburg, Hermann-Herder-Str. 7, Freiburg, Germany
- 2Institute of Physiology, Faculty of Medicine, University of Freiburg, Hermann-Herder-Str. 7, Freiburg, Germany. [email protected]
- 3Department of Neurophysiology, Keio University School of Medicine, Tokyo, Japan
- 4Department of Clinical Chemistry, Sahlgrenska University Hospital, Gothenburg, Sweden
- 5Department of Laboratory Medicine, Institute for Biomedicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
- 6Biozentrum of the University of Basel, Basel, Switzerland
- 7Logopharm GmbH, Schlossstr. 14, March-Buchheim, Germany
- 8Wallenberg Centre for Molecular and Translational Medicine, University of Gothenburg, Gothenburg, Sweden
- 9Center for Basics in NeuroModulation, Breisacherstr. 4, Freiburg, Germany. [email protected]
- 10Institute of Physiology, Faculty of Medicine, University of Freiburg, Hermann-Herder-Str. 7, Freiburg, Germany. [email protected]
- 11Signalling Research Centres BIOSS and CIBSS, Schänzlestr. 18, Freiburg, Germany. [email protected]
Abstract
Synapses, prototypic sites for neuronal communication, are key to brain function. Their organization and properties are instructed by synaptic cell adhesion molecules (sCAMs) that may operate independently or in coordination through yet unknown linker proteins. Here, we used multi-epitope affinity-purifications combined with quantitative mass spectrometry and immuno-EM to comprehensively map synaptic protein networks in the mouse brain. We identify a pre-synaptic core-module assembled from the major sCAMs, Neurexins1-3 and LAR-type receptor protein-tyrosine-phosphatases (PTPRs), and the previously uncharacterized tetraspanins T178A/B. These ternary Neurexin-T178-PTPR complexes form through their trans-membrane domains and assemble during biogenesis in the ER. Loss of T178B leads to module destabilization, accompanied by strong reduction of LAR-PTPRs and re-distribution of synaptic Neurexins. At synapses, the Neurexin-T178-PTPR module recruits stable trans-synaptic protein networks thereby interlinking machineries of the pre-synaptic active zone and establishing stable associations with post-synaptic neurotransmitter receptors. This work uncovers a widely distributed core-module for synaptic adhesion and trans-synaptic signaling in the mammalian brain.
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BibTeX
@article{thivaios2026ternary,
title = {{Ternary Neurexin-T178-PTPR complexes represent a pre-synaptic core-module of neuronal synapse organization}},
author = {Spyros Thivaios and Jochen Schwenk and Aline Bréchet and Sami Boudkkazi and Nithya Sethumadhavan and Phil Henneken and Eriko Miura and Ayumi Hayashi and Maciej K. Kocylowski and Alexander Haupt and Debora Kaminski and Dietmar Schreiner and Agata Nowacka and Jean-Baptiste van den Broucke and Ákos Kulik and Uwe Schulte and Fredrik H. Sterky and Michisuke Yuzaki and Peter Scheiffele and Bernd Fakler},
journal = {Nature Communications},
year = {2026},
month = sep,
doi = {10.1038/s41467-026-77377-4},
url = {https://doi.org/10.1038/s41467-026-77377-4},
note = {CC BY},
}
RIS
TY - JOUR
TI - Ternary Neurexin-T178-PTPR complexes represent a pre-synaptic core-module of neuronal synapse organization
AU - Spyros Thivaios
AU - Jochen Schwenk
AU - Aline Bréchet
AU - Sami Boudkkazi
AU - Nithya Sethumadhavan
AU - Phil Henneken
AU - Eriko Miura
AU - Ayumi Hayashi
AU - Maciej K. Kocylowski
AU - Alexander Haupt
AU - Debora Kaminski
AU - Dietmar Schreiner
AU - Agata Nowacka
AU - Jean-Baptiste van den Broucke
AU - Ákos Kulik
AU - Uwe Schulte
AU - Fredrik H. Sterky
AU - Michisuke Yuzaki
AU - Peter Scheiffele
AU - Bernd Fakler
PY - 2026
DA - 2026/09/05
JO - Nature Communications
DO - 10.1038/s41467-026-77377-4
UR - https://doi.org/10.1038/s41467-026-77377-4
AB - Synapses, prototypic sites for neuronal communication, are key to brain function. Their organization and properties are instructed by synaptic cell adhesion molecules (sCAMs) that may operate independently or in coordination through yet unknown linker proteins. Here, we used multi-epitope affinity-purifications combined with quantitative mass spectrometry and immuno-EM to comprehensively map synaptic protein networks in the mouse brain. We identify a pre-synaptic core-module assembled from the major sCAMs, Neurexins1-3 and LAR-type receptor protein-tyrosine-phosphatases (PTPRs), and the previously uncharacterized tetraspanins T178A/B. These ternary Neurexin-T178-PTPR complexes form through their trans-membrane domains and assemble during biogenesis in the ER. Loss of T178B leads to module destabilization, accompanied by strong reduction of LAR-PTPRs and re-distribution of synaptic Neurexins. At synapses, the Neurexin-T178-PTPR module recruits stable trans-synaptic protein networks thereby interlinking machineries of the pre-synaptic active zone and establishing stable associations with post-synaptic neurotransmitter receptors. This work uncovers a widely distributed core-module for synaptic adhesion and trans-synaptic signaling in the mammalian brain.
SN - 2041-1723
ER -