Protein-tyrosine phosphatase-sigma is a novel member of the functional family of alpha-latrotoxin receptors.
Receptor-like protein-tyrosine phosphatase sigma (PTPvarsigma) is essential for neuronal development and function. Here we report that PTPvarsigma is a target of alpha-latrotoxin, a strong stimulator of neuronal exocytosis. alpha-Latrotoxin binds to the cell adhesion-like extracellular region of PTPvarsigma. This binding results in the stimulation of exocytosis. The toxin-binding site is located in the C-terminal part of the PTPvarsigma ectodomain and includes two fibronectin type III repeats. The intracellular catalytic domains of PTPvarsigma are not required for the alpha-latrotoxin binding and secretory response triggered by the toxin in chromaffin cells. These features of PTPvarsigma resemble two other previously described alpha-latrotoxin receptors, neurexin and CIRL. Thus, alpha-latrotoxin represents an unusual example of the neurotoxin that has three independent, equally potent, and yet structurally distinct targets. The known structural and functional characteristics of PTPvarsigma, neurexin, and CIRL suggest that they define a functional family of neuronal membrane receptors with complementary or converging roles in presynaptic function via a mechanism that involves cell-to-cell and cell-to-matrix interaction.
Department of Pharmacology, New York University School of Medicine, New York, New York 10016, USA.
Valery
V
Krasnoperov
Mary A
MA
Bittner
Wenjun
W
Mo
Leonid
L
Buryanovsky
Thomas A
TA
Neubert
Ronald W
RW
Holz
Konstantin
K
Ichtchenko
Alexander G
AG
Petrenko
D000818:Animals; D001665:Binding Sites; D015153:Blotting, Western; D001921:Brain / Q000378:metabolism; D019556:COS Cells; D002118:Calcium / Q000378:metabolism; D002384:Catalysis; D002462:Cell Membrane / Q000378:metabolism; D019439:Chromaffin Cells / Q000378:metabolism; D003432:Cross-Linking Reagents / Q000494:pharmacology; D003902:Detergents / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004591:Electrophoresis, Polyacrylamide Gel; D005089:Exocytosis; D017353:Gene Deletion; D006023:Glycoproteins; D019382:Human Growth Hormone / Q000494:pharmacology; D006801:Humans; D008024:Ligands; D013058:Mass Spectrometry; D008565:Membrane Proteins; D008957:Models, Genetic; D016296:Mutagenesis; D009154:Mutation; D009419:Nerve Tissue Proteins / Q000378:metabolism; D009474:Neurons / Q000378:metabolism; D009479:Neuropeptides; D010957:Plasmids / Q000378:metabolism; D011233:Precipitin Tests; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D017027:Protein Tyrosine Phosphatases / Q000737:chemistry* / Q000502:physiology*; D051381:Rats; D054623:Receptor-Like Protein Tyrosine Phosphatases, Class 2; D043562:Receptors, G-Protein-Coupled; D018000:Receptors, Peptide / Q000737:chemistry* / Q000302:isolation & purification / Q000378:metabolism; D011994:Recombinant Proteins / Q000378:metabolism; D012685:Sepharose / Q000494:pharmacology; D016622:Silver Staining; D014162:Transfection
C467733:ADGRL1 protein, human; D003432:Cross-Linking Reagents; D003902:Detergents; D006023:Glycoproteins; D008024:Ligands; D008565:Membrane Proteins; D009419:Nerve Tissue Proteins; D009479:Neuropeptides; D043562:Receptors, G-Protein-Coupled; D018000:Receptors, Peptide; D011994:Recombinant Proteins; C034800:alpha-latrotoxin receptor; C112162:neurexophilin; D019382:Human Growth Hormone; D012685:Sepharose; C516883:PTPRS protein, human; D017027:Protein Tyrosine Phosphatases; D054623:Receptor-Like Protein Tyrosine Phosphatases, Class 2; D002118:Calcium