Fibrinogen Mitaka II: a hereditary dysfibrinogen with defective thrombin binding caused by an A alpha Glu-11 to Gly substitution.
A new type of A alpha Glu-11 to Gly substitution has been identified in a congenitally abnormal fibrinogen, fibrinogen Mitaka II, derived from a 14-year-old female suffering from easy bruising since childhood. Plasma of the patient and fibrinogen purified therefrom were found to clot slowly by thrombin but in a normal fashion by ancrod, a thrombin-like snake venom enzyme. The ancrod-clotted fibrin gels were normally solid and turbid, whereas the thrombin-clotted gels were initially fragile and transparent but became gradually normalized during further incubation. On reverse-phase high-performance liquid chromatography, there was an additional peptide group eluted distinctly later than the corresponding normal fibrinopeptide A in the clot-liquor of the patient's samples. Sequence analysis of these aberrant peptides and isolated A alpha chains of the patient's fibrinogen showed that Glu at position 11 of the abnormal A alpha chain had been replaced by Gly. Studies using 125I-labeled thrombin showed that the binding with thrombin was evidently reduced for her fibrinogen and the aberrant fibrinopeptide A as compared with that for the normal controls, indicating that A alpha Glu-11 may be critical for the fibrinogen-thrombin interaction. Indeed, A alpha Glu-11 of fibrinogen has recently been proposed to stabilize the local conformation, including the beta-turn, and to form a salt bridge between its side-chain carboxyl group and the guanidino group of Arg-173 of thrombin based on crystallographic analyses using analogs of fibrinopeptide A complexed with thrombin (Stubb et al, Eur J Biochem 206:187, 1992 and Martin et al, J Biol Chem 267:7911, 1992).
Niwa
K
K
Division of Hemostasis and Thrombosis Research, Jichi Medical School, Tochigi, Japan.
Yaginuma
A
A
Nakanishi
M
M
Wada
Y
Y
Sugo
T
T
Asakura
S
S
Watanabe
N
N
Matsuda
M
M
D000293:Adolescent; D000595:Amino Acid Sequence; D000721:Ancrod / Q000378:metabolism; D005260:Female; D015241:Fibrinogens, Abnormal / Q000235:genetics* / Q000378:metabolism*; D005344:Fibrinopeptide A / Q000737:chemistry / Q000302:isolation & purification; D005971:Glutamates; D018698:Glutamic Acid; D005998:Glycine; D006801:Humans; D007700:Kinetics; D008297:Male; D008969:Molecular Sequence Data; D017354:Point Mutation; D013917:Thrombin / Q000378:metabolism*
D015241:Fibrinogens, Abnormal; D005971:Glutamates; C084911:fibrinogen Mitaka II; D005344:Fibrinopeptide A; D018698:Glutamic Acid; D000721:Ancrod; D013917:Thrombin; D005998:Glycine