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Vol. 12, Issue 10, 2947-2960, October 2001
and
*Molecular Neuropathobiology and §Cell
Biophysics Laboratories, Imperial Cancer Research Fund, WC2A 3PX
London, United Kingdom; and Tetanus (TeNT) is a zinc protease that blocks neurotransmission by
cleaving the synaptic protein vesicle-associated membrane protein/synaptobrevin. Although its intracellular catalytic
activity is well established, the mechanism by which this neurotoxin
interacts with the neuronal surface is not known. In this study, we
characterize p15s, the first plasma membrane TeNT binding proteins and
we show that they are glycosylphosphatidylinositol-anchored
glycoproteins in nerve growth factor (NGF)-differentiated PC12 cells,
spinal cord cells, and purified motor neurons. We identify p15 as
neuronal Thy-1 in NGF-differentiated PC12 cells. Fluorescence lifetime imaging microscopy measurements confirm the close association of the
binding domain of TeNT and Thy-1 at the plasma membrane. We find that
TeNT is recruited to detergent-insoluble lipid microdomains on the
surface of neuronal cells. Finally, we show that cholesterol depletion
affects a raft subpool and blocks the internalization and intracellular
activity of the toxin. Our results indicate that TeNT interacts with
target cells by binding to lipid rafts and that cholesterol is required
for TeNT internalization and/or trafficking in neurons.
Richard Dimbleby Department
of Cancer Research, St. Thomas' Hospital, SE1 7EH London, United
Kingdom
Present address: Department of Biological
Sciences, Imperial College of Science, Technology, and Medicine,
Exhibition Rd., SW7 2AY London, UK.
Corresponding authors. E-mail addresses:
g.schiavo{at}icrf.icnet.uk and j.herreros{at}ic.ac.uk.
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