Molecular basis for the fibrinogen structure and functions-Analysis Of hereditary dysfibrinogens and their application to the study
Grant-in-Aid for Scientific Research (B).
|Allocation Type||Single-year Grants |
|Research Institution||Jichi Medical School |
MATSUDA Michio Division of Cell and Molecular Medicine, Center for Molecular Medicien, Jichi Medical School, Professor, 医学部, 教授 (50048980)
MIMURO Jun Division of Cell and Molecular Medicine, Center for Molecular Medicien, Jichi Medical School, Instructor, 医学部, 講師 (10221607)
SUGO Teruko Division of Cell and Molecular Medicine, Center for Molecular Medicien, Jichi Medical School, Instructor, 医学部, 講師 (60183844)
SAKATA Yoichi Division of Cell and Molecular Medicine, Center for Molecular Medicien, Jichi Medical School, Associate professor., 医学部, 助教授 (40129028)
MADOIWA Seiji Division of Cell and Molecular Medicine, Center for Molecular Medicien, Jichi Medical School, Instructor, 医学部, 講師 (70296119)
|Project Period (FY)
1999 – 2000
Completed (Fiscal Year 2000)
|Budget Amount *help
¥3,300,000 (Direct Cost: ¥3,300,000)
Fiscal Year 2000: ¥1,500,000 (Direct Cost: ¥1,500,000)
Fiscal Year 1999: ¥1,800,000 (Direct Cost: ¥1,800,000)
|Keywords||fibrinogen / hereditary dysfibrinogen / bleeding tendency / fibrinogen structure / extra carbohydrate / fibrin nets / fibrin ultra-structure / gene analysis / 余剩糖鎖 / 遺伝性異常フィブリノゲン / フィブリノゲン異常症 / 血栓性素因 / 糖付加構造 / 電顕学的分析 / フィブリンの超微細構造 / 停止コドンの消失|
1. The Molecular Mechanisms of Extra Asn-linked Oligosaccharides
By transmission electron microscopy (TEM), we have studied the role of extra sugar moiteis linked to Asn residues due to creation of an Asn-X-Thr/Ser type sequence owing to an amino acid substitution
In fibrinogen Asahi, the extra sugar moities linked to γAsn-308 residues due to a γMet-310 to Thr substitution are suggested to interfere with the E-D binding and cross-linking of the fibrin γ-chain. Indeed, removal of the sugar moities resulted in the formation of well ordered fibrin networks with appropriate branching, although the D : D association still remained owing to the point mutation. Thus, we conclude that the extra sugar moieties are largely responsible for the functional abnormality in this dysfibrinogen.
On the contrary, a high proportion of disialylated oligosaccharide in fibrinogen Lima (78%) generates electric repulsive forces due to sialic acids and disturbs lateral association of fibrin protofibrils on polymer
ization. Removal of sialic acids alone lead to formation normal fibrin ultra structures as has been suggested by biochemical studies.
2. Characterization of a unique dysfibrinogen, fibrinogen Osaka VI with a 12 residue extension of the Bb-chain.
In a dysfibrinogen derived from a 36-year-old woman who had suffered from severe bleeding on two occasions of childbirth, we have identified a 12-residue extension of the Bβ-chain due to a transition of (TAG) for stop to (AAG) for Lys. Thus, additional 36 base pairs are translated. Interestingly, one or two disulfide bridges are formed between two corresponding Cys residues at the second position from the new C-terminus, leading to formation of end-linked fibrinogen homodimers, which are aligned either in parallel or in tandem as demonstrated by TEM.Inclusion of these fibrinogen dimers in protofibrils seems to be related to the formation of highly branched and fragile fibrin clots.
The results have been reported in Blood 96(12) : 3779-3785, 2000 and also in the Annals of New York Academy of Sciences, in press. Less
Report (3 results)
Research Products (33 results)