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J. Biol. Chem., Vol. 276, Issue 20, 16611-16616, May 18, 2001
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From the Department of Pathology and Laboratory Medicine and the
British Columbia Research Institute for Children's and Women's
Health, University of British Columbia, Vancouver,
British Columbia V5Z 4H4, Canada
Islet amyloid deposits are a
characteristic pathologic lesion of the pancreas in type 2 diabetes and
are composed primarily of the islet beta cell peptide islet amyloid
polypeptide (IAPP or amylin) as well as the basement membrane heparan
sulfate proteoglycan perlecan. Impaired processing of the IAPP
precursor has been implicated in the mechanism of islet amyloid
formation. The N- and C-terminal cleavage sites where pro-IAPP
is processed by prohormone convertases contain a series of basic
amino acid residues that we hypothesized may interact with heparan
sulfate proteoglycans. This possibility was tested using affinity
chromatography by applying synthetic fragments of pro-IAPP to
heparin-agarose and heparan sulfate-Sepharose. An N-terminal human
pro-IAPP fragment (residues 1-30) was retained by both heparin-agarose
and heparan sulfate-Sepharose, eluting at 0.18 M NaCl
at pH 7.5. Substitution of alanine residues for two basic residues in
the N-terminal cleavage site abolished heparin and heparan sulfate
binding activity. At pH 5.5, the affinity of the wild-type peptide for
heparin/heparan sulfate was increased, implying a role for histidine
residues at positions 6 and 28 of pro-IAPP. A C-terminal pro-IAPP
fragment (residues 41-67) had no specific affinity for either heparin
or heparan sulfate, and the N- or C-terminal fragments had only weak
affinity for chondroitin sulfate. These data suggest that monomeric
N-terminal human pro-IAPP contains a heparin binding domain that is
lost during normal processing of pro-IAPP.
Identification of a Heparin Binding Domain in the N-terminal
Cleavage Site of Pro-islet Amyloid Polypeptide
IMPLICATIONS FOR ISLET AMYLOID FORMATION*
and
*
This work was supported by Medical Research Council of
Canada (now Canadian Institutes of Health Research) Grant MT-14682.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.
Supported by a Graduate Studentship from the British Columbia
Research Institute for Children's & Women's Health.
§
Supported by a New Investigator award from the Canadian
Institutes for Health Research. To whom correspondence
should be addressed: British Columbia Research Institute for
Children's and Women's Health, 950 West 28th Ave., Vancouver, British
Columbia V5Z 4H4, Canada. Tel.: 604-875-2490; Fax: 604-875-3120;
E-mail: verchere@interchange.ubc.ca.
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