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

Abstract

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.

TANGO2 deficiency as a cause of neurodevelopmental delay with indirect effects on mitochondrial energy metabolism

“…Established cultures were further passaged in DMEM media without antibiotics. Lentivirus particles were packaged in HEK293 cells in DMEM media, as described, 6 and applied to fibroblasts 1.5 to 2 days prior to analysis. For live microscopy, cells were grown in poly-L-lysine-coated glass bottom dishes (CELLview, Greiner Bio-One).…”

Genetic correlates of evolutionary adaptations in cognitive functional brain networks and their relationship to human cognitive functioning and disease

“…CBLN1 encodes a cerebellum-specific precursor protein, precerebellin, and is important for synapse integrity and synaptic plasticity together with NRXN1 and GRID2 52 . CA10, which belongs to the carbonic anhydrase family of zinc metalloenzymes, is believed to be central in the development of the central neural system by coordinating neurexins, which are presynaptic celladhesion molecules that bind to diverse postsynaptic ligands, and are linked to neuropsychiatric disorders 53 . KCNB2 regulates potassium voltage-gated channel and is known to be essential in regulating neurotransmitter release and neuronal excitability 54 .…”

Structures of neurexophilin–neurexin complexes reveal a regulatory mechanism of alternative splicing

“…The b-neurexins include only the C-terminal region of a-neurexins from the LNS6 domain onward. Nrxn1c, in turn, lacks all LNS domains; its extracellular region contains only the C-terminal stalk region that is conserved in all neurexins (Sterky et al, 2017). All neurexins are embedded in the membrane by a single transmembrane region followed by a short (~55 residue) cytoplasmic tail.…”