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 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.
Narizhneva
Natalya V
NV
Department of Molecular Cardiology, Cleveland Clinic Foundation, 9500 Euclid Avenue, Cleveland, Ohio 44195, USA.
Byers-Ward
Vicky J
VJ
Quinn
Martin J
MJ
Zidar
Frank J
FJ
Plow
Edward F
EF
Topol
Eric J
EJ
Byzova
Tatiana V
TV
D001216:Asparagine; D002942:Circular Dichroism; D014644:Genetic Variation; D006801:Humans; D009203:Myocardial Infarction / Q000453:epidemiology / Q000235:genetics*; D010974:Platelet Aggregation / Q000235:genetics / Q000502:physiology; D020641:Polymorphism, Single Nucleotide; D012307:Risk Factors; D012694:Serine; D019700:Thrombospondin 1 / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism*
D019700:Thrombospondin 1; D012694:Serine; D001216:Asparagine