Molecular and Functional Differences Induced in Thrombospondin-1 by the Single Nucleotide Polymorphism Associated with the Risk of Premature, Familial Myocardial Infarction
A serine (Ser-700) amino acid rather than an asparagine (Asn-700) at residue 700 of thrombospondin-1 has been linked to an increased risk for development of premature, familial heart attacks. We now have identified both functional and structural differences between the Ser-700 and Asn-700 thrombospo...
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Published in | The Journal of biological chemistry Vol. 279; no. 20; pp. 21651 - 21657 |
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Main Authors | , , , , , , |
Format | Journal Article |
Language | English |
Published |
United States
American Society for Biochemistry and Molecular Biology
14.05.2004
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Subjects | |
Online Access | Get full text |
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Summary: | A serine (Ser-700) amino acid rather than an asparagine (Asn-700) at residue 700 of thrombospondin-1 has been linked to an
increased risk for development of premature, familial heart attacks. We now have identified both functional and structural
differences between the Ser-700 and Asn-700 thrombospondin-1 variants. The Ser-700 variant increased the rate and extent of
platelet aggregation and showed increased surface expression on platelets compared with the Asn-700 variant. These differences
could be ascribed to an enhanced interaction of the Ser-700 variant with fibrinogen on the platelet surface and are consistent
with a prothrombotic phenotype in Ser-700 individuals. The Ser-700 variant thrombospondin-1 was conformationally more labile
than the Asn-700 variant as demonstrated by increased susceptibility to proteolytic digestion and enhanced susceptibility
to unfolding by denaturants. These data suggest a potential molecular and cellular basis for a genetic risk factor associated
with early onset myocardial infarction. |
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Bibliography: | ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 Recipient of an American Heart Association Fellowship (0325229B). To whom correspondence may be addressed: Dept. of Cardiovascular Medicine, Cleveland Clinic Foundation, 9500 Euclid Ave., Cleveland, OH 44195. Tel.: 216-445-9490; Fax: 216-445-9595; E-mail: topole@ccf.org. To whom correspondence may be addressed: Joseph J. Jacobs Ctr. for Thrombosis and Vascular Biology, Dept. of Molecular Cardiology, Cardiology and Taussig Cancer Ctr., Cleveland Clinic Foundation, 9500 Euclid Ave., Cleveland, OH 44195. Tel.: 216-445-9490; Fax: 216-445-9595. |
ISSN: | 0021-9258 1083-351X |
DOI: | 10.1074/jbc.M311090200 |