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J Biol Chem, Vol. 274, Issue 1, 59-66, January 1, 1999
, and
From the Molecular Neuropathobiology and Synaptotagmins constitute a large family of
membrane proteins characterized by their distinct distributions and
different biochemical features. Genetic evidence suggests that members
of this protein family are likely to function as calcium sensors in
calcium-regulated events in neurons, although the precise molecular mechanism remains ill defined. Here we demonstrate that different synaptotagmin isoforms (Syt I, II, and IV) are present in the same
synaptic vesicle population from rat brain cortex. In addition, Syt I
and II co-localize on the same small synaptic vesicle (SSV), and they
heterodimerize in the presence of calcium with a concentration dependence resembling that of the starting phase of SSV exocytosis (EC50 = 6 ± 4 µM). The
association between Syt I and Syt II was demonstrated by
immunoprecipitation of the native proteins and the recombinant
cytoplasmic domains and by using fluorescence resonance energy transfer
(FRET). Although a subpopulation of SSV containing Syt I and IV can be
isolated, these two isoforms do not show a
calcium-dependent interaction. These results suggest that
the self-association of synaptotagmins with different calcium binding
features may create a variety of calcium sensors characterized by
distinct calcium sensitivities. This combinatorial hypothesis predicts
that the probability of a single SSV exocytic event is determined, in
addition to the gating properties of the presynaptic calcium channels,
by the repertoire and relative abundance of distinct synaptotagmin
isoforms present on the SSV surface.
Cell
Biophysics Laboratories, Imperial Cancer Research Fund, 44 Lincoln's
Inn Fields, London WC2A 3PX, United Kingdom
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