The functional and clinical significance of the Met-->Thr substitution in Kringle IV type 10 of apolipoprotein(a).
Lipoprotein(a) [Lp(a)], an independent risk factor for the development of atherosclerosis, contains an apolipoprotein(a) [apo(a)] moiety covalently linked to a LDL moiety. Apo(a) is a glycoprotein homologous to plasminogen as it contains multiple repeats of a lysine binding domain resembling plasminogen kringle IV (K.IV). The multiple K.IV repeats can be differentiated in ten types that show a variation in their lysine binding capacity. Since K.IV type 10 shows the highest conservation of the amino acids postulated to form the lysine binding pocket, this kringle is suggested to be the main lysine binding site of apo(a). Recently, a T-->C polymorphism in the apo(a)-gene was reported, leading to a Met-->Thr substitution at amino acid position 66 of K.IV type 10, in the vicinity of the postulated lysine binding pocket. To investigate the significance of this substitution on some in vitro characteristics of Lp(a), the affinity for lysine-Sepharose and the binding affinity for limited plasmin digested des AA fibrin (Desafib-X) of the two subtypes was determined using plasma of donors homozygous for the polymorphism. These studies revealed a large heterogeneity in the binding characteristics, irrespective of the subtype. The comparison of the allele frequencies of this polymorphism in 155 patients having symptomatic atherosclerosis versus 153 normolipidemic controls revealed no significant differences. In conclusion, this study suggests that the presence of either a Met66 or a Thr66 residue in K.IV type 10 of apo(a) has no consequences for the binding characteristics of Lp(a) toward lysine-Sepharose or Desafib-X, nor is it associated with the presence of symptomatic atherosclerosis.
Department of Clinical Chemistry, University Hospital, Utrecht, The Netherlands. J.Prins@lab.azu.nl
J
J
Prins
Y Y
YY
van der Hoek
T H
TH
Biesheuvel
F R
FR
Leus
H J
HJ
van Rijn
J J
JJ
Kastelein
D000328:Adult; D000483:Alleles; D019943:Amino Acid Substitution / Q000235:genetics*; D001054:Apolipoproteins A / Q000737:chemistry* / Q000235:genetics*; D001161:Arteriosclerosis / Q000235:genetics; D016022:Case-Control Studies; D002784:Cholesterol / Q000032:analysis; D005260:Female; D006801:Humans; D018082:Kringles / Q000235:genetics*; D017270:Lipoprotein(a) / Q000032:analysis / Q000378:metabolism; D008239:Lysine / Q000378:metabolism; D008297:Male; D008715:Methionine / Q000235:genetics*; D008875:Middle Aged; D011110:Polymorphism, Genetic / Q000235:genetics; D013912:Threonine / Q000235:genetics*
D001054:Apolipoproteins A; D017270:Lipoprotein(a); D013912:Threonine; D002784:Cholesterol; D008715:Methionine; D008239:Lysine