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J. Biol. Chem., Vol. 277, Issue 7, 5134-5144, February 15, 2002
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From the Secreted Frizzled-related protein-1 (sFRP-1), a
soluble protein that binds to Wnts and modulates Wnt signaling,
contains an N-terminal domain homologous to the putative Wnt-binding
site of Frizzled (Fz domain) and a C-terminal heparin-binding domain with weak homology to netrin. Both domains are cysteine-rich, having 10 and 6 cysteines in the Fz and heparin-binding domains, respectively. In
this study, the disulfide linkages of recombinant sFRP-1 were
determined. Numbering sFRP-1 cysteines sequentially from the N
terminus, the five disulfide linkages in the Fz domain are 1-5, 2-4,
3-8, 6-10, and 7-9, consistent with the disulfide pattern determined
for homologous domains of several other proteins. The disulfide
linkages of the heparin-binding domain are 11-14, 12-15, and 13-16.
This latter set of assignments provides experimental verification of
one of the disulfide patterns proposed for netrin (NTR) modules and
thereby supports the prediction that the C-terminal heparin-binding
domain of sFRP-1 is an NTR-type domain. Interestingly, two subsets of
sFRPs appear to have alternate disulfide linkage patterns compared with
sFRP-1, one of which involves the loss of a disulfide due to deletion
of a single cysteine from the NTR module, whereas the remaining
cysteine may pair with a new cysteine introduced in the Fz domain of
the protein. Analysis of glycosylation sites showed that sFRP-1
contains a relatively large carbohydrate moiety on
Asn172 (~2.8 kDa), whereas
Asn262, the second potential N-linked
glycosylation site, is not modified. No O-linked
carbohydrate groups were detected. There was evidence of heterogeneous
proteolytic processing at both the N and C termini of the recombinant
protein. The predominant N terminus was Ser31, although
minor amounts of the protein with Asp41 and
Phe50 as the N termini were observed. The major C-terminal
processing event was removal of the terminal amino acid
(Lys313) with only a trace amount of unprocessed protein detected.
Disulfide Bond Assignments of Secreted Frizzled-related Protein-1
Provide Insights about Frizzled Homology and Netrin Modules*
,
Wistar Institute,
Philadelphia, Pennsylvania 19104 and the § Laboratory of
Cellular and Molecular Biology, Center for Cancer Research, NCI,
National Institutes of Health, Bethesda, Maryland 20892
*
This work was supported in part by National Institutes of
Health Grants CA74294 and CA10815 (to D. W. S.).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: the Wistar
Institute, 3601 Spruce St., Philadelphia, PA 19104. Tel.: 215-898-3972; Fax: 215-898-0664; E-mail: speicher@wistar.upenn.edu.
Copyright © 2002 by The American Society for Biochemistry and Molecular Biology, Inc.
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