Carbonic anhydrase-related protein CA10 is an evolutionarily conserved pan-neurexin ligand

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 114; no. 7; pp. E1253 - E1262
• Main Authors: Sterky, Fredrik H., Trotter, Justin H., Lee, Sung-Jin, Recktenwald, Christian V., Du, Xiao, Zhou, Bo, Zhou, Peng, Schwenk, Jochen, Fakler, Bernd, Südhof, Thomas C.
• Format: Journal Article
• Language: English
• Published: United States National Academy of Sciences 14.02.2017
• Series: PNAS Plus
• Subjects: alpha; Amino Acid Sequence; Animals; beta-neurexins; Biological Sciences; brain; Brain - metabolism; Car10; Car11; cell adhesion; Cell adhesion & migration; cell-surface proteins; Conserved Sequence; domain; gene; Genes; HEK293 Cells; Humans; Ligands; Medical Biotechnology; Medicinsk bioteknologi; Membranes; Mice; Molecules; Nerve Tissue Proteins - metabolism; Neural Cell Adhesion Molecules - metabolism; Neurons - metabolism; phosphatases; PNAS Plus; Proteins; receptor; Science & Technology - Other Topics; synapse; synapse formation; tyrosine; viii; Car11; synapse; cell adhesion; Car10
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.1621321114

Establishment, specification, and validation of synaptic connections are thought to be mediated by interactions between pre- and postsynaptic cell-adhesion molecules. Arguably, the best-characterized transsynaptic interactions are formed by presynaptic neurexins, which bind to diverse postsynaptic ligands. In a proteomic screen of neurexin-1 (Nrxn1) complexes immunoisolated from mouse brain, we identified carbonic anhydrase-related proteins CA10 and CA11, two homologous, secreted glycoproteins of unknown function that are predominantly expressed in brain. We found that CA10 directly binds in a cis configuration to a conserved membrane-proximal, extracellular sequence of α- and β-neurexins. The CA10–neurexin complex is stable and stoichiometric, and results in formation of intermolecular disulfide bonds between conserved cysteine residues in neurexins and CA10. CA10 promotes surface expression of α- and β-neurexins, suggesting that CA10 may form a complex with neurexins in the secretory pathway that facilitates surface transport of neurexins. Moreover, we observed that the Nrxn1 gene expresses from an internal 3′ promoter a third isoform, Nrxn1γ, that lacks all Nrxn1 extracellular domains except for the membrane-proximal sequences and that also tightly binds to CA10. Our data expand the understanding of neurexin-based transsynaptic interaction networks by providing further insight into the interactions nucleated by neurexins at the synapse.