Intrinsically Unfolded Alpha-C Region Of Fibrinogen is Major Contributor to Mechanical Strength of Fibrin Fibers

Abstract

Background. Fibrinogen is the key mechanical protein in blood coagulation since it is the building block of fibrin fibers, and these 100 nm thick fibers provide mechanical and structural stability to blood clots as they stem the flow of blood. Fibrinogen has two large, intrinsically unfolded regions, termed alphaC regions, which comprise 27% of its molecular weight. The role of these unfolded regions has long puzzled scientists. We hypothesize that they contribute significantly to the mechanical properties of fibrin fibers, which, in turn, determine the stability of blood clots. Methods. We used a nano-mechanical manipulation method, based on a combined atomic force and optical microscope, to determine the mechanical properties of native fibrin fibers, and of fibers formed from a variant in which the alphaC region was truncated. Results. Compared to native fibrin fibers, fibers formed from the truncated variant showed dramatically different mechanical properties. The extensibility (fracture strain) was reduced by a factor of 1.6 (from 1.96 to 1.26); the fracture stress was reduced by a factor of 22 (from 13.7 MPa to 0.61 MPa); and the modulus (stiffness) decreased by a factor of 5.8 (from 6.11 MPa to 1.05 MPa). Conclusion. The large, intrinsically unfolded alphaC region of fibrinogen is a major contributor to the mechanical strength of fibrin fibers, and thus to the strength of blood clots. These findings have significant implications for haemostasis and thrombosis.