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Fibrinogen Mitaka II: a hereditary dysfibrinogen with defective thrombin binding caused by an A alpha Glu-11 to Gly
K Niwa1, A Yaginuma, M Nakanishi
1Division of Hemostasis and Thrombosis Research, Jichi Medical School, Tochigi, Japan.
Abstract:
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isolated A alpha chains of the patient's fibrinogen showed that Glu at position 11 of the abnormal A alpha chain had been replaced by Gly.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).
Insights
A novel fibrinogen mutation (A alpha Glu-11 to Gly) impairs thrombin binding, causing abnormal blood clotting. This fibrinogen Mitaka II discovery highlights the critical role of A alpha Glu-11 in fibrinogen function.
Area of Science:
- Biochemistry
- Hematology
- Molecular Biology
Background:
- Congenital fibrinogen abnormalities can lead to bleeding disorders.
- Fibrinogen Mitaka II, identified in a patient with easy bruising, presents a unique A alpha chain substitution.
Observation:
- The patient's plasma and purified fibrinogen exhibited slow clotting with thrombin but normal clotting with ancrod.
- Thrombin-induced clots were initially fragile and transparent, unlike the normal, solid clots formed with ancrod.
- Aberrant fibrinopeptide A was detected, eluting later than normal fibrinopeptide A.
Findings:
- A substitution of Glutamic acid (Glu) at position 11 to Glycine (Gly) in the A alpha chain of fibrinogen was identified.
- Fibrinogen Mitaka II showed reduced binding affinity to thrombin compared to normal fibrinogen.
- The A alpha Glu-11 residue is crucial for effective fibrinogen-thrombin interaction.
Implications:
- This finding underscores the importance of A alpha Glu-11 in maintaining fibrinogen's conformation and interaction with thrombin.
- Understanding this mutation provides insights into the molecular mechanisms of blood coagulation and potential therapeutic targets.