科研之友
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摘要
The flexible C-terminal parts of fibrinogen's A alpha chains named the alpha C regions have been shown to play a role in fibrin self-assembly, although many aspects of their structure and functions remain unknown. To examine the involvement of the alpha C regions in the early stages of fibrin formation, we used high-resolution atomic force microscopy to image fibrinogen and oligomeric fibrin. Plasma-purified full-length human fibrinogen or des-alpha C fibrinogen lacking most of the alpha C regions, untreated or treated with thrombin, was imaged. Up to 80% of the potentially existing alpha C regions were visualized and quantified; they were highly heterogeneous in their length and configurations. Conversion of fibrinogen to fibrin was accompanied by an increase in the incidence and length of the alpha C regions as well as transitions from more compact conformations, such as a globule on a string, to extended and more flexible offshoots. Concurrent dynamic turbidimetry, confocal microscopy, and scanning electron microscopy revealed that trimming of the alpha C regions slowed down fibrin formation, which correlated with longer protofibrils, thinner fibers, and a denser network. No structural distinctions, except for the incidence of the alpha C regions, were revealed in the laterally aggregated protofibrils made of the full-length or des-alpha C fibrinogens, suggesting a pure kinetic effect of the alpha C regions on the fibrin architecture. This work provides a structural molecular basis for the promoting role of the alpha C regions in the early stages of fibrin self-assembly and reveals this stage of fibrin formation as a potential therapeutic target to modulate the structure and mechanical properties of blood clots.
- 出版日期2017-9-28
