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J Biol Chem, Vol. 273, Issue 28, 17351-17360, July 10, 1998
From the Departments of Neurology and Physiology, Graduate Programs
in Neuroscience and Cell Biology, University of California School
of Medicine, San Francisco, California 94143-0435
Specific transport proteins mediate the packaging
of neurotransmitters into secretory vesicles and consequently require
targeting to the appropriate intracellular compartment. To identify
residues in the neuron-specific vesicular monoamine transporter (VMAT2) responsible for endocytosis, we examined the effect of amino
(NH2-) and carboxyl (COOH-)-terminal mutations on
steady state distribution and internalization. Deletion of a critical
COOH-terminal domain sequence (AKEEKMAIL) results in accumulation of
VMAT2 at the plasma membrane and a 50% reduction in endocytosis.
Site-directed mutagenesis shows that replacement of the
isoleucine-leucine pair within this sequence by alanine-alanine alone
reduces endocytosis by 50% relative to wild type VMAT2. Furthermore,
the KEEKMAIL sequence functions as an internalization signal when
transferred to the plasma membrane protein Tac, and the mutation of the
isoleucine-leucine pair also abolishes internalization of this protein.
The closely related vesicular acetylcholine transporter (VAChT)
contains a similar di-leucine sequence within the cytoplasmic
COOH-terminal domain that when mutated results in accumulation of VAChT
at the plasma membrane. The VAChT di-leucine sequence also confers
internalization when appended to two other proteins and in one of these
chimeras, conversion of the di-leucine sequence to di-alanine reduces
the internalization rate by 50%. Both VMAT2 and VAChT thus use
leucine-based signals for efficient endocytosis and as such are the
first synaptic vesicle proteins known to use this motif for
trafficking.
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