Molecular and Functional Differences Induced in Thrombospondin-1 by the Single Nucleotide Polymorphism Associated with the Risk of Premature, Familial Myocardial Infarction

• Published in: The Journal of biological chemistry Vol. 279; no. 20; pp. 21651 - 21657
• Main Authors: Narizhneva, Natalya V, Byers-Ward, Vicky J, Quinn, Martin J, Zidar, Frank J, Plow, Edward F, Topol, Eric J, Byzova, Tatiana V
• Format: Journal Article
• Language: English
• Published: United States American Society for Biochemistry and Molecular Biology 14.05.2004
• Subjects: Asparagine; Circular Dichroism; Genetic Variation; Humans; Myocardial Infarction - epidemiology; Myocardial Infarction - genetics; Platelet Aggregation - genetics; Platelet Aggregation - physiology; Polymorphism, Single Nucleotide; Risk Factors; Serine; Thrombospondin 1 - chemistry; Thrombospondin 1 - genetics; Thrombospondin 1 - metabolism
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.M311090200

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.