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Sci Adv. 2020 Feb 19;6(8):eaax5783. doi: 10.1126/sciadv.aax5783. eCollection 2020 Feb.

Stitching the synapse: Cross-linking mass spectrometry into resolving synaptic protein interactions.

Author information

1
Department of Molecular and Cellular Neurobiology, Center for Neurogenomics and Cognitive Research, Amsterdam Neuroscience, Vrije Universiteit Amsterdam, Amsterdam, Netherlands.
2
Department of Medical Epidemiology and Biostatistics, Karolinska Institute, Stockholm, Sweden.
3
Departments of Genetics and Psychiatry, University of North Carolina, Chapel Hill, NC, USA.
4
Department of Structural Biology, Leibniz-Forschungsinstitut für Molekulare Pharmakologie (FMP), Berlin, Germany.
5
Department of Functional Genomics, Center for Neurogenomics and Cognitive Research, Amsterdam Neuroscience, Vrije Universiteit Amsterdam, Amsterdam, Netherlands.
6
Department of Chemical Biology, Leibniz-Forschungsinstitut für Molekulare Pharmakologie (FMP), Berlin, Germany.
7
Biomolecular Mass Spectrometry and Proteomics, Bijvoet Center for Biomolecular Research, and Utrecht Institute for Pharmaceutical Sciences, Utrecht University, Utrecht, Netherlands.

Abstract

Synaptic transmission is the predominant form of communication in the brain. It requires functionally specialized molecular machineries constituted by thousands of interacting synaptic proteins. Here, we made use of recent advances in cross-linking mass spectrometry (XL-MS) in combination with biochemical and computational approaches to reveal the architecture and assembly of synaptic protein complexes from mouse brain hippocampus and cerebellum. We obtained 11,999 unique lysine-lysine cross-links, comprising connections within and between 2362 proteins. This extensive collection was the basis to identify novel protein partners, to model protein conformational dynamics, and to delineate within and between protein interactions of main synaptic constituents, such as Camk2, the AMPA-type glutamate receptor, and associated proteins. Using XL-MS, we generated a protein interaction resource that we made easily accessible via a web-based platform (http://xlink.cncr.nl) to provide new entries into exploration of all protein interactions identified.

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