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J. Biol. Chem., Vol. 277, Issue 23, 21027-21040, June 7, 2002
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From the Department of Genetics and the ¶ Center for Cell and
Molecular Imaging, Yale University School of Medicine,
New Haven, Connecticut 06510
The yeast plasma-membrane
H+-ATPase, encoded by PMA1, is delivered
to the cell surface via the secretory pathway and has recently emerged
as an excellent system for identifying quality control mechanisms along
the pathway. In the present study, we have tracked the biogenesis of
Pma1-G381A, a misfolded mutant form of the H+-ATPase.
Although this mutant ATPase is arrested transiently in the peripheral
endoplasmic reticulum, it does not become a substrate for endoplasmic
reticulum-associated degradation nor does it appear to stimulate an
unfolded protein response. Instead, Pma1-G381A accumulates in
Kar2p-containing vesicular-tubular clusters that resemble those
previously described in mammalian cells. Like their mammalian
counterparts, the yeast vesicular-tubular clusters may correspond to
specific exit ports from the endoplasmic reticulum, since Pma1-G381A
eventually escapes from them (still in a misfolded, trypsin-sensitive
form) to reach the plasma membrane. By comparison with wild-type
ATPase, Pma1-G381A spends a short half-life at the plasma membrane
before being removed and sent to the vacuole for degradation in a
process that requires both End4p and Pep4p. Finally, in a separate set
of experiments, Pma1-G381A was found to impose its phenotype on
co-expressed wild-type ATPase, transiently retarding the wild-type
protein in the ER and later stimulating its degradation in the vacuole.
Both effects serve to lower the steady-state amount of wild-type ATPase
in the plasma membrane and, thus, can explain the co-dominant genetic
behavior of the G381A mutation. Taken together, the results of this
study establish Pma1-G381A as a useful new probe for the yeast
secretory system.
Quality Control in the Yeast Secretory
Pathway
A MISFOLDED PMA1 H+-ATPase REVEALS TWO
CHECKPOINTS*
,
*
This work was supported by National Institutes of Health
Research Grant GM15761 (to C. W. S.) and by Yale Brown-Coxe
Postdoctoral Fellowship and Philippe Foundation Postdoctoral Fellowship
(to T. F.).The costs of publication of this
article were defrayed in part by the
payment of page charges. The article
must therefore be hereby marked
"advertisement" in
accordance with 18 U.S.C. Section
1734 solely to indicate this fact.
Current address: IBMIG, Campus Sciences, Université de
Poitiers, 40 Avenue du Recteur Pineau, 86 022 Poitiers Cedex, France.
§
To whom correspondence and reprint requests should be addressed:
Dept. of Genetics Yale University School of Medicine, 333 Cedar St.,
New Haven, CT 06510. Tel.: 203-785-2690; Fax: 203-785-7227; E-mail:
cw.slaymanlab@yale.edu.
Copyright © 2002 by The American Society for Biochemistry and Molecular Biology, Inc.
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