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J. Cell Biol.,
Volume 139, Number 4, November 17, 1997 917-927
* Department of Neurobiology, Harvard Medical School, Boston, Massachusetts 02115; and Synaptic vesicles are concentrated in the distal axon, far from the site of protein synthesis. Integral
membrane proteins destined for this organelle must
therefore make complex targeting decisions. Short
amino acid sequences have been shown to act as targeting signals directing proteins to a variety of intracellular locations. To identify synaptic vesicle targeting sequences and to follow the path that proteins travel en
route to the synaptic vesicle, we have used a defective
herpes virus amplicon expression system to study the
targeting of a synaptobrevin-transferrin receptor (SB-TfR) chimera in cultured hippocampal neurons. Addition of the cytoplasmic domain of synaptobrevin onto
human transferrin receptor was sufficient to retarget
the transferrin receptor from the dendrites to presynaptic sites in the axon. At the synapse, the SB-TfR chimera did not localize to synaptic vesicles, but was instead found in an organelle with biochemical and
functional characteristics of an endosome. The chimera
recycled in parallel with synaptic vesicle proteins demonstrating that the nerve terminal efficiently sorts
transmembrane proteins into different pathways. The
synaptobrevin sequence that controls targeting to the
presynaptic endosome was not localized to a single, 10-
amino acid region of the molecule, indicating that this
targeting signal may be encoded by a more distributed
structural conformation. However, the chimera could
be shifted to synaptic vesicles by deletion of amino acids 61-70 in synaptobrevin, suggesting that separate signals encode the localization of synaptobrevin to the
synapse and to the synaptic vesicle.
Department of Genetics, Harvard
Medical School, McLean Hospital, Belmont, Massachusetts 02178
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