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J. Biol. Chem., Vol. 277, Issue 33, 29686-29697, August 16, 2002
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From the Calnexin and calreticulin are
membrane-bound and soluble chaperones, respectively, of the endoplasmic
reticulum (ER) which interact transiently with a broad spectrum of
newly synthesized glycoproteins. In addition to sharing substantial
sequence identity, both calnexin and calreticulin bind to
monoglucosylated oligosaccharides of the form
Glc1Man5-9GlcNAc2, interact
with the thiol oxidoreductase, ERp57, and are capable of acting as
chaperones in vitro to suppress the aggregation of
non-native proteins. To understand how these diverse
functions are coordinated, we have localized the lectin, ERp57 binding,
and polypeptide binding sites of calnexin and calreticulin. Recent
structural studies suggest that both proteins consist of a globular
domain and an extended arm domain comprised of two sequence motifs
repeated in tandem. Our results indicate that the primary lectin site
of calnexin and calreticulin resides within the globular domain, but
the results also point to a much weaker secondary site within the arm
domain which lacks specificity for monoglucosylated oligosaccharides.
For both proteins, a site of interaction with ERp57 is centered on the
arm domain, which retains ~50% of binding compared with full-length
controls. This site is in addition to a
Zn2+-dependent site located within the globular
domain of both proteins. Finally, calnexin and calreticulin
suppress the aggregation of unfolded proteins via a polypeptide binding
site located within their globular domains but require the arm domain
for full chaperone function. These findings are integrated into a model
that describes the interaction of glycoprotein folding intermediates
with calnexin and calreticulin.
Localization of the Lectin, ERp57 Binding, and Polypeptide
Binding Sites of Calnexin and Calreticulin*
§,,
Department of Biochemistry, University of
Toronto, Toronto, Ontario M5S 1A8, Canada and the ¶ Department of
Biochemistry, McGill University,
Montreal, Quebec H3A 2B2, Canada
*
This work was supported in part by the National Cancer
Institute of Canada with funds from the Canadian Cancer 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: Dept. of
Biochemistry, Medical Sciences Bldg., University of Toronto, Toronto, Ontario M5S 1A8, Canada. Tel.: 416-978-2546; Fax: 416-978-8548; E-mail: david.williams@utoronto.ca.
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