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 α- and β-neurexins, polymorphic neuron-specific cell surface proteins, as neuronal dystroglycan receptors. The extracellular sequences of α- and β-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 α-latrotoxin; this toxin competes with dystroglycan for binding, suggesting overlapping binding sites on neurexins for dystroglycan and α-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.
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23 July 2001
Article|
July 16 2001
A stoichiometric complex of neurexins and dystroglycan in brain
Shuzo Sugita,
Shuzo Sugita
1Center for Basic Neuroscience, Department of Molecular Genetics, and Howard Hughes Medical Institute, The University of Texas Southwestern Medical Center at Dallas, Dallas, TX 75390
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Fumiaki Saito,
Fumiaki Saito
2Department of Physiology and Biophysics, Department of Neurology, and Howard Hughes Medical Institute, University of Iowa, Iowa City, IA 52242
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Jiong Tang,
Jiong Tang
1Center for Basic Neuroscience, Department of Molecular Genetics, and Howard Hughes Medical Institute, The University of Texas Southwestern Medical Center at Dallas, Dallas, TX 75390
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Jakob Satz,
Jakob Satz
2Department of Physiology and Biophysics, Department of Neurology, and Howard Hughes Medical Institute, University of Iowa, Iowa City, IA 52242
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Kevin Campbell,
Kevin Campbell
2Department of Physiology and Biophysics, Department of Neurology, and Howard Hughes Medical Institute, University of Iowa, Iowa City, IA 52242
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Thomas C. Südhof
Thomas C. Südhof
1Center for Basic Neuroscience, Department of Molecular Genetics, and Howard Hughes Medical Institute, The University of Texas Southwestern Medical Center at Dallas, Dallas, TX 75390
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Shuzo Sugita
1Center for Basic Neuroscience, Department of Molecular Genetics, and Howard Hughes Medical Institute, The University of Texas Southwestern Medical Center at Dallas, Dallas, TX 75390
Fumiaki Saito
2Department of Physiology and Biophysics, Department of Neurology, and Howard Hughes Medical Institute, University of Iowa, Iowa City, IA 52242
Jiong Tang
1Center for Basic Neuroscience, Department of Molecular Genetics, and Howard Hughes Medical Institute, The University of Texas Southwestern Medical Center at Dallas, Dallas, TX 75390
Jakob Satz
2Department of Physiology and Biophysics, Department of Neurology, and Howard Hughes Medical Institute, University of Iowa, Iowa City, IA 52242
Kevin Campbell
2Department of Physiology and Biophysics, Department of Neurology, and Howard Hughes Medical Institute, University of Iowa, Iowa City, IA 52242
Thomas C. Südhof
1Center for Basic Neuroscience, Department of Molecular Genetics, and Howard Hughes Medical Institute, The University of Texas Southwestern Medical Center at Dallas, Dallas, TX 75390
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: [email protected]
*
Abbreviations used in this paper: CL, CIRL/latrophilin; ES, embryonic stem; GST, glutathione S-transferase; HC, heavy chain; LC, light chain; LG, laminin G; LNS, laminin-neurexin–sex hormone–binding globulin; TFMS, trifluoromethanesulfonic acid.
Received:
May 01 2001
Revision Received:
June 07 2001
Accepted:
June 11 2001
Online ISSN: 1540-8140
Print ISSN: 0021-9525
The Rockefeller University Press
2001
J Cell Biol (2001) 154 (2): 435–446.
Article history
Received:
May 01 2001
Revision Received:
June 07 2001
Accepted:
June 11 2001
Citation
Shuzo Sugita, Fumiaki Saito, Jiong Tang, Jakob Satz, Kevin Campbell, Thomas C. Südhof; A stoichiometric complex of neurexins and dystroglycan in brain . J Cell Biol 23 July 2001; 154 (2): 435–446. doi: https://doi.org/10.1083/jcb.200105003
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