title: Neurexophilins form a conserved family of neuropeptide-like glycoproteins.
abstract: Neurexophilin was discovered as a neuronal glycoprotein that is copurified with neurexin Ialpha during affinity chromatography on immobilized alpha-latrotoxin (Petrenko et al., 1996). We have now investigated how neurexophilin interacts with neurexins, whether it is post-translationally processed by site-specific cleavage similar to neuropeptides, and whether related neuropeptide-like proteins are expressed in brain. Our data show that mammalian brains contain four genes for neurexophilins the products of which share a common structure composed of five domains: an N-terminal signal peptide, a variable N-terminal domain, a highly conserved central domain that is N-glycosylated, a short linker region, and a conserved C-terminal domain that is cysteine-rich. When expressed in pheochromocytoma (PC12) cells with a replication-deficient adenovirus, neurexophilin 1 was rapidly N-glycosylated and then slowly processed to a smaller mature form, probably by endoproteolytic cleavage. Similar expression experiments in other neuron-like cells and in fibroblastic cells revealed that N-glycosylation of neurexophilin 1 occurred in all cell types tested, whereas proteolytic processing was observed only in neuron-like cells. Finally, only recombinant neurexin Ialpha and IIIalpha but not neurexin Ibeta interacted with neurexophilin 1 and were preferentially bound to the processed mature form of neurexophilin. Together our data demonstrate that neurexophilins form a family of related glycoproteins that are proteolytically processed after synthesis and bind to alpha-neurexins. The structure and characteristics of neurexophilins indicate that they function as neuropeptides that may signal via alpha-neurexins.
authors.affiliation: Howard Hughes Medical Institute and Department of Molecular Genetics, The University of Texas Southwestern Medical School, Dallas, Texas 75235, USA.
authors.forename: M
authors.initials: M
authors.lastname: Missler
authors.forename: T C
authors.initials: TC
authors.lastname: Südhof
mesh_terms: D000818:Animals; D019556:COS Cells / Q000201:enzymology; D002417:Cattle; D003001:Cloning, Molecular; D010450:Endopeptidases / Q000378:metabolism; D015870:Gene Expression; D006023:Glycoproteins / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D051379:Mice; D008969:Molecular Sequence Data; D005810:Multigene Family / Q000235:genetics*; D009419:Nerve Tissue Proteins / Q000378:metabolism; D009474:Neurons / Q000737:chemistry* / Q000187:drug effects / Q000201:enzymology; D009479:Neuropeptides / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D016716:PC12 Cells; D017434:Protein Structure, Tertiary; D051381:Rats; D017386:Sequence Homology, Amino Acid; D013111:Spider Venoms / Q000494:pharmacology
chemical_list: D006023:Glycoproteins; D009419:Nerve Tissue Proteins; D009479:Neuropeptides; D013111:Spider Venoms; C112162:neurexophilin; C020763:alpha-latrotoxin; D010450:Endopeptidases