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Vol. 57, Issue 2, 232-242, February 2000
Forschungsinstitut für Molekulare Pharmakologie (G.K., R.H.,
A.O., C.R., W.R., R.S.); and Institut für Pharmakologie, Freie
Universität Berlin, Berlin, Germany (W.R.).
We have previously shown a conserved glutamate/dileucine motif
(335ELRSLL340) in the
intracellular C terminus of the vasopressin V2 receptor (V2 receptor) to be essential for receptor transport from
the endoplasmic reticulum (ER) to the Golgi apparatus. The motif may represent a transport signal that is recognized by a component of ER to
Golgi vesicles. Alternatively, it may be necessary for transport-competent receptor folding to pass the quality-control system
of the ER. To assess these two possibilities, we constructed a receptor
fragment that allows transport studies independent of full-length
receptor folding. Transmembrane domains II-VII were deleted, thereby
fusing the intracellular C terminus to the first cytoplasmic loop. The
mutations that impaired transport of the full-length receptor were
introduced, and receptor fragments were localized in transiently
transfected HEK 293 cells. All mutant receptor fragments were
detectable at the plasma membrane, demonstrating that the
glutamate/dileucine motif does not function as a small, linear
vesicular transport signal. Instead, our data strongly suggest that
this motif is required for transport-competent folding of the
full-length receptor. To assess the underlying conformational features,
a three-dimensional homology model of the V2 receptor was
computed. Our model predicts that the glutamate/dileucine motif
contributes to a U-like loop within the intracellular C terminus.
Residue Leu339 may be required for folding back the
intracellular C terminus to residue Leu62 of the first
cytoplasmic loop. We characterized the naturally occurring L62P and
L62-R64 mutations in the first cytoplasmic loop and show that they
lead to transport-defective full-length V2 receptors that
are retained in the ER, consistent with the structure model.
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