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Vol. 12, Issue 4, 1093-1101, April 2001
and
*University of Cambridge, Wellcome Trust Center for Molecular
Mechanisms in Disease, Cambridge Institute for Medical Research,
and Department of Clinical Biochemistry, Cambridge CB2 2XY, United
Kingdom; and Secretory proteins that fail to fold in the endoplasmic reticulum
(ER) are transported back to the cytosol and degraded by proteasomes.
It remains unclear how the cell distinguishes between folding
intermediates and misfolded proteins. We asked whether misfolded
secretory proteins are covalently modified in the ER before export. We
found that a fraction of mutant alpha-factor precursor, but not the
wild type, was progressively O-mannosylated in
microsomes and in intact yeast cells by protein
O-mannosyl transferase 2 (Pmt2p).
O-Mannosylation increased significantly in vitro under
ER export conditions, i.e., in the presence of ATP and cytosol, and
this required export-proficient Sec61p in the ER membrane. Deletion of
PMT2, however, did not abrogate mutant alpha-factor
precursor degradation but, rather, enhanced its turnover in intact
yeast cells. In vitro, O-mannosylated mutant
alpha-factor precursor was stable and protease protected, and a
fraction was associated with Sec61p in the ER lumen. Thus, prolonged ER
residence allows modification of exposed O-mannosyl
acceptor sites in misfolded proteins, which abrogates misfolded protein
export from the ER at a posttargeting stage. We conclude that there is
a limited window of time during which misfolded proteins can be removed from the ER before they acquire inappropriate modifications that can
interfere with disposal through the Sec61 channel.
Lehrstuhl für Zellbiologie und
Pflanzenphysiologie, Universität Regensburg, 93053 Regensburg,
Germany
Corresponding author. E-mail:
kbr20{at}cam.ac.uk.
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