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Vol. 11, Issue 9, 2973-2985, September 2000
*Molecular Medicine Division, Oregon Health Sciences University,
Portland, Oregon 97201; The topology of most eukaryotic polytopic membrane proteins is
established cotranslationally in the endoplasmic reticulum (ER) through
a series of coordinated translocation and membrane integration events.
For the human aquaporin water channel AQP1, however, the initial
four-segment-spanning topology at the ER membrane differs from the
mature six-segment-spanning topology at the plasma membrane. Here we
use epitope-tagged AQP1 constructs to follow the transmembrane (TM)
orientation of key internal peptide loops in Xenopus
oocyte and cell-free systems. This analysis revealed that AQP1
maturation in the ER involves a novel topological reorientation of
three internal TM segments and two peptide loops. After the synthesis
of TMs 4-6, TM3 underwent a 180-degree rotation in which TM3
C-terminal flanking residues were translocated from their initial
cytosolic location into the ER lumen and N-terminal flanking residues
underwent retrograde translocation from the ER lumen to the cytosol.
These events convert TM3 from a type I to a type II topology and
reposition TM2 and TM4 into transmembrane conformations consistent with
the predicted six-segment-spanning AQP1 topology. AQP1 topological
reorientation was also associated with maturation from a
protease-sensitive conformation to a protease-resistant structure with
water channel function. These studies demonstrate that initial protein
topology established via cotranslational translocation events in the ER
is dynamic and may be modified by subsequent steps of folding and/or maturation.
Department of Medicine,
University of Pennsylvania, Philadelphia, Pennsylvania 19104;
and §Cardiovascular Research Unit, University of
California, San Francisco, California 94143
Present address: Genetics and Biochemistry
Branch, National Institutes of Health, Bethesda, MD 20892.
Corresponding author. E-mail address:
skachw{at}ohsu.edu.
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