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J. Biol. Chem., Vol. 276, Issue 19, 15975-15982, May 11, 2001
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From the University of Manchester, School of Biological Sciences,
2.205 Stopford Building, Manchester M13 9PT, United Kingdom
The addition of glycosylphosphatidylinositol
(GPI) anchors to proteins occurs by a transamidase-catalyzed reaction
mechanism soon after completion of polypeptide synthesis and
translocation. We show that placental alkaline phosphatase becomes
efficiently GPI-anchored when translated in the presence of
semipermeabilized K562 cells but is not GPI-anchored in cell lines
defective in the transamidase subunit hGpi8p. By studying the synthesis
of placental alkaline phosphatase, we demonstrate that folding of the
protein is not influenced by the addition of a GPI anchor and
conversely that GPI anchor addition does not require protein folding.
These results demonstrate that folding of the ectodomain and GPI
addition are two distinct processes and can be mutually exclusive. When
GPI addition is prevented, either by synthesis of the protein in the
presence of cell lines defective in GPI addition or by mutation of the
GPI carboxyl-terminal signal sequence cleavage site, the substrate
forms a prolonged association with the transamidase subunit hGpi8p. The
ability of the transamidase to recognize and associate with GPI anchor
signal sequences provides an explanation for the retention of
GPI-anchored protein within the ER in the absence of GPI anchor addition.
Early Events in Glycosylphosphatidylinositol Anchor Addition
SUBSTRATE PROTEINS ASSOCIATE WITH THE TRANSAMIDASE SUBUNIT
Gpi8p*
*
This work was supported by Medical Research Council Grants
G9722981 and G9722026 and by a grant from the Royal Society.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.
To whom correspondence should be addressed. Tel.: 44-61-275-5103;
Fax: 44-61-275-5082; E-mail: neil.bulleid@man.ac.uk.
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