Linked Life Data

9856994

Source:http://linkedlifedata.com/resource/pubmed/id/9856994

Statements in which the resource exists as a subject.
PredicateObject
rdf:type
lifeskim:mentions
pubmed:issue
52
pubmed:dateCreated
1999-2-3
pubmed:abstractText
alpha-Neurexins (Ialpha, IIalpha, and IIIalpha) are receptor-like proteins expressed in hundreds of isoforms on the neuronal cell surface. The extracellular domains of alpha-neurexins are composed of six LNS repeats, named after homologous sequences in the Laminin A G domain, Neurexins, and Sex hormone-binding globulin, with three interspersed epidermal growth factor-like domains. Purification of neurexin Ialpha revealed that it is tightly complexed to a secreted glycoprotein called neurexophilin 1. Neurexophilin 1 is a member of a family of at least four genes and resembles a neuropeptide, suggesting a function as an endogenous ligand for alpha-neurexins. We have now used recombinant proteins and knockout mice to investigate which isoforms and domains of different neurexins and neurexophilins interact with each other. We show that neurexophilins 1 and 3 but not 4 (neurexophilin 2 is not expressed in rodents) bind to a single individual LNS domain, the second overall LNS domain in all three alpha-neurexins. Although this domain is alternatively spliced, all splice variants bind, suggesting that alternative splicing does not regulate binding. Using homologous recombination to disrupt the neurexophilin 1 gene, we generated mutant mice that do not express detectable neurexophilin 1 mRNA. Mice lacking neurexophilin 1 are viable with no obvious morbidity or mortality. However, homozygous mutant mice exhibit male sterility, probably because homologous recombination resulted in the co-insertion into the neurexophilin gene of herpes simplex virus thymidine kinase, which is known to cause male sterility. In the neurexophilin 1 knockout mice, neurexin Ialpha is complexed with neurexophilin 3 but not neurexophilin 4, suggesting that neurexophilin 1 is redundant with neurexophilin 3 and that neurexophilins 1 and 3 but not 4 bind to neurexins. This hypothesis was confirmed using expression experiments. Our data reveal that the six LNS and three epidermal growth factor domains of neurexins are independently folding ligand-binding domains that may interact with distinct targets. The results support the notion that neurexophilins represent a family of extracellular signaling molecules that interact with multiple receptors including all three alpha-neurexins.
pubmed:grant
pubmed:language
eng
pubmed:journal
pubmed:citationSubset
IM
pubmed:chemical
pubmed:status
MEDLINE
pubmed:month
Dec
pubmed:issn
0021-9258
pubmed:author
pubmed:issnType
Print
pubmed:day
25
pubmed:volume
273
pubmed:owner
NLM
pubmed:authorsComplete
Y
pubmed:pagination
34716-23
pubmed:dateRevised
2007-11-14
pubmed:meshHeading
pubmed-meshheading:9856994-Amino Acid Sequence, pubmed-meshheading:9856994-Animals, pubmed-meshheading:9856994-Binding Sites, pubmed-meshheading:9856994-Glycoproteins, pubmed-meshheading:9856994-Infertility, Male, pubmed-meshheading:9856994-Ligands, pubmed-meshheading:9856994-Male, pubmed-meshheading:9856994-Membrane Proteins, pubmed-meshheading:9856994-Mice, pubmed-meshheading:9856994-Mice, Knockout, pubmed-meshheading:9856994-Molecular Sequence Data, pubmed-meshheading:9856994-Nerve Tissue Proteins, pubmed-meshheading:9856994-Neuropeptides, pubmed-meshheading:9856994-Protein Binding, pubmed-meshheading:9856994-Protein Folding, pubmed-meshheading:9856994-Recombinant Fusion Proteins, pubmed-meshheading:9856994-Repetitive Sequences, Amino Acid, pubmed-meshheading:9856994-Serine Endopeptidases
pubmed:year
1998
pubmed:articleTitle
Neurexophilin binding to alpha-neurexins. A single LNS domain functions as an independently folding ligand-binding unit.
pubmed:affiliation
Howard Hughes Medical Institute, University of Texas Southwestern Medical School, Dallas, Texas 75235, USA.
pubmed:publicationType
Journal Article, Research Support, U.S. Gov't, P.H.S., Research Support, Non-U.S. Gov't