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J Biol Chem, Vol. 275, Issue 9, 6328-6336, March 3, 2000
From the Department of Biochemistry, University of Wisconsin,
Madison, Wisconsin 53706
The plasma membrane soluble
N-ethylmaleimide-sensitive factor attachment protein
receptor (SNARE) proteins syntaxin and synaptosome-associated protein
of 25 kDa (SNAP25) and the vesicle SNARE protein vesicle-associated membrane protein (VAMP) are essential for a late
Ca2+-dependent step in regulated exocytosis,
but their precise roles and regulation by Ca2+ are poorly
understood. Botulinum neurotoxin (BoNT) E, a protease that cleaves
SNAP25 at Arg180-Ile181, completely inhibits
this late step in PC12 cell membranes, whereas BoNT A, which cleaves
SNAP25 at Gln197-Arg198, is only partially
inhibitory. The difference in toxin effectiveness was found to result
from a reversal of BoNT A but not BoNT E inhibition by elevated
Ca2+ concentrations. BoNT A treatment essentially increased
the Ca2+ concentration required to activate exocytosis,
which suggested a role for the C terminus of SNAP25 in the
Ca2+ regulation of exocytosis. Synaptotagmin, a proposed
Ca2+ sensor for exocytosis, was found to bind SNAP25 in a
Ca2+-stimulated manner.
Ca2+-dependent binding was abolished by BoNT E
treatment, whereas BoNT A treatment increased the Ca2+
concentration required for binding. The C terminus of SNAP25 was also
essential for Ca2+-dependent synaptotagmin
binding to SNAP25·syntaxin and SNAP25·syntaxin·VAMP SNARE
complexes. These results clarify classical observations on the
Ca2+ reversal of BoNT A inhibition of neurosecretion, and
they suggest that an essential role for the C terminus of SNAP25 in
regulated exocytosis is to mediate
Ca2+-dependent interactions between
synaptotagmin and SNARE protein complexes.
The C Terminus of SNAP25 Is Essential for
Ca2+-dependent Binding of Synaptotagmin to
SNARE Complexes*
,
*
This work was supported in part by National Institutes of
Health Research Grants DK25861 and DK40428 (to T. F. J. M.).The costs of publication of this
article were defrayed in part by the
payment of page charges. The article
must therefore be hereby marked
"advertisement" in
accordance with 18 U.S.C. Section
1734 solely to indicate this fact.
Supported by National Institutes of Health Predoctoral Training
Grant GM07215.
§
To whom correspondence should be addressed: Dept. of Biochemistry,
University of Wisconsin, 433 Babcock Dr., Madison, WI 53706. Tel.:
608-263-2427; Fax: 608-262-3453; E-mail:
tfmartin@facstaff.wisc.edu.
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C. A. Earles, J. Bai, P. Wang, and E. R. Chapman The tandem C2 domains of synaptotagmin contain redundant Ca2+ binding sites that cooperate to engage t-SNAREs and trigger exocytosis J. Cell Biol., September 17, 2001; 154(6): 1117 - 1124. [Abstract] [Full Text] [PDF]
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