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Published online 16 July 2001. doi:10.1083/jcb.200105003
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© The Rockefeller University Press, 0021-9525/2001/7/435 $5.00
The Journal of Cell Biology, Volume 154, Number 2, July 23, 2001 435-446

Article

A stoichiometric complex of neurexins and dystroglycan in brain



Shuzo Sugita1, Fumiaki Saito2, Jiong Tang1, Jakob Satz2, Kevin Campbell2 and Thomas C. Südhof1

1 Center for Basic Neuroscience, Department of Molecular Genetics, and Howard Hughes Medical Institute, The University of Texas Southwestern Medical Center at Dallas, Dallas, TX 75390
2 Department of Physiology and Biophysics, Department of Neurology, and Howard Hughes Medical Institute, University of Iowa, Iowa City, IA 52242

Address correspondence to Thomas C. Südhof, Center for Basic Neuroscience, UT Southwestern Medical Center, 6000 Harry Hines Blvd. NA4.118, Dallas, TX 75390-9111. Tel.: (214) 648-1876. Fax: (214) 648-1879. E-mail: thomas.sudhof{at}utsouthwestern.edu

In nonneuronal cells, the cell surface protein dystroglycan links the intracellular cytoskeleton (via dystrophin or utrophin) to the extracellular matrix (via laminin, agrin, or perlecan). Impairment of this linkage is instrumental in the pathogenesis of muscular dystrophies. In brain, dystroglycan and dystrophin are expressed on neurons and astrocytes, and some muscular dystrophies cause cognitive dysfunction; however, no extracellular binding partner for neuronal dystroglycan is known. Regular components of the extracellular matrix, such as laminin, agrin, and perlecan, are not abundant in brain except in the perivascular space that is contacted by astrocytes but not by neurons, suggesting that other ligands for neuronal dystroglycan must exist. We have now identified {alpha}- and ß-neurexins, polymorphic neuron-specific cell surface proteins, as neuronal dystroglycan receptors. The extracellular sequences of {alpha}- and ß-neurexins are largely composed of laminin-neurexin–sex hormone–binding globulin (LNS)/laminin G domains, which are also found in laminin, agrin, and perlecan, that are dystroglycan ligands. Dystroglycan binds specifically to a subset of the LNS domains of neurexins in a tight interaction that requires glycosylation of dystroglycan and is regulated by alternative splicing of neurexins. Neurexins are receptors for the excitatory neurotoxin {alpha}-latrotoxin; this toxin competes with dystroglycan for binding, suggesting overlapping binding sites on neurexins for dystroglycan and {alpha}-latrotoxin. Our data indicate that dystroglycan is a physiological ligand for neurexins and that neurexins' tightly regulated interaction could mediate cell adhesion between brain cells.

Key Words: neurexin; dystroglycan; synapse; LNS domain; laminin


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