Carbonic anhydrase-related protein CA10 is an evolutionarily conserved pan-neurexin ligand.
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 acisconfiguration 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.
Department of Molecular and Cellular Physiology, Stanford University School of Medicine, Stanford, CA 94305; fredrik.sterky@gu.se tcs1@stanford.edu.
Fredrik H
0000-0001-8881-0523
FH
Sterky
Department of Molecular and Cellular Physiology, Stanford University School of Medicine, Stanford, CA 94305.
Justin H
JH
Trotter
Department of Molecular and Cellular Physiology, Stanford University School of Medicine, Stanford, CA 94305.
Sung-Jin
SJ
Lee
Department of Medical Biochemistry, University of Gothenburg, SE-405 30 Gothenburg, Sweden.
Christian V
CV
Recktenwald
Department of Molecular and Cellular Physiology, Stanford University School of Medicine, Stanford, CA 94305.
Xiao
X
Du
Department of Molecular and Cellular Physiology, Stanford University School of Medicine, Stanford, CA 94305.|Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, CA 94305.
Bo
B
Zhou
Department of Molecular and Cellular Physiology, Stanford University School of Medicine, Stanford, CA 94305.|Howard Hughes Medical Institute, Stanford University School of Medicine, Stanford, CA 94305.
Peng
P
Zhou
Institute of Physiology, University of Freiburg, 79104 Freiburg, Germany.
Jochen
J
Schwenk
Institute of Physiology, University of Freiburg, 79104 Freiburg, Germany.
Bernd
B
Fakler
Department of Molecular and Cellular Physiology, Stanford University School of Medicine, Stanford, CA 94305; fredrik.sterky@gu.se tcs1@stanford.edu.|Howard Hughes Medical Institute, Stanford University School of Medicine, Stanford, CA 94305.
Thomas C
TC
Südhof
D000595:Amino Acid Sequence; D000818:Animals; D001921:Brain / Q000378:metabolism*; D002135:Calcium-Binding Proteins; D017124:Conserved Sequence; D057809:HEK293 Cells; D006801:Humans; D008024:Ligands; D051379:Mice; D009419:Nerve Tissue Proteins / Q000378:metabolism*; D019006:Neural Cell Adhesion Molecules / Q000378:metabolism*; D009474:Neurons / Q000378:metabolism*
C512815:CA10 protein, human; D002135:Calcium-Binding Proteins; C512819:Car10 protein, mouse; C512820:Car11 protein, mouse; D008024:Ligands; D009419:Nerve Tissue Proteins; D019006:Neural Cell Adhesion Molecules; C527193:Nrxn1 protein, mouse
Car10; Car11; cell adhesion; synapse