Central to cell motility is the actin filament severing activity of cofilin, which is essential to the viability of cell. However, it is unknown how cofilin severs an actin filament. I determined that cofilin decreases the elastic modulus of actin filaments, which makes them more flexible. Based on these results, I proposed that cofilin severs actin filaments when partially decorated by accumulating stress from thermally-driven shape fluctuations at bare (rigid) and cofilin-decorated (compliant) boundaries. This mechanics-based severing model predicts that changes in actin filament compliance due to cofilin binding affect severing activity. I tested this prediction by evaluating how the severing activities of vertebrate and yeast cofilactin scale correlate with an increase in the flexibility of actin filaments by cofilin. Indeed, severing is attenuated when cofilin binds but does not increase actin filament flexibility. I also revealed that severing events are associated with local bending and fragmentation when deformations attain a critical angle. The critical severing angle at boundaries between bare and cofilin-decorated segments is smaller than in bare or fully-decorated filaments. These results support a mechanism for actin filament severing by cofilin in which mechanical asymmetry promotes local stress accumulation and fragmentation at boundaries of bare and cofilin-decorated segments, analogous to failure of some non-protein materials.
|Advisor:||Cruz, Enrique M. De La|
|School Location:||United States -- Connecticut|
|Source:||DAI-B 73/12(E), Dissertation Abstracts International|
|Subjects:||Biochemistry, Biomechanics, Biophysics|
|Keywords:||Actin filament, Colfilin, Deformation, Fracture, Severing|
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