Fibrinogen Mitaka II: a hereditary dysfibrinogen with defective thrombin binding caused by an A alpha Glu-11 to Gly substitution.

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isolated A alpha chains of the patient's fibrinogen showed that Glu at position 11 of the abnormal A alpha chain had been replaced by Gly.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).

journal_name

Blood

journal_title

Blood

authors

Niwa K,Yaginuma A,Nakanishi M,Wada Y,Sugo T,Asakura S,Watanabe N,Matsuda M

subject

Has Abstract

pub_date

1993-12-15 00:00:00

pages

3658-63

issue

12

eissn

0006-4971

issn

1528-0020

journal_volume

82

pub_type

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