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Phosphorylation facilitates the integrin binding of filamin under force
Harvey S Chen1, Kevin S Kolahi, Mohammad R K Mofrad
1Molecular Cell Biomechanics Laboratory, Department of Bioengineering, University of California, Berkeley, California, USA.
Biophysical Journal
|December 17, 2009
Summary
Filamin-A
Area of Science:
- Biochemistry
- Molecular Biology
- Biophysics
Background:
- Filamins are crucial actin-binding proteins involved in cytoskeletal integrity and mechanochemical signal transduction.
- Human filamins function as dimers, characterized by an actin-binding domain and 24 immunoglobulin (Ig)-like repeats.
- The Ig-like repeats 19-21 (IgFLNa-R19-R21) of filamin-A are critical, housing the integrin binding site but are sterically hindered by IgFLNa-R20.
Purpose of the Study:
- To investigate the regulatory mechanisms of filamin-A, specifically the roles of force and phosphorylation on its integrin binding site.
- To elucidate how mechanical force and phosphorylation at Ser(2152) modulate the autoinhibition of IgFLNa-R21.
Main Methods:
- Utilized molecular dynamics (MD) simulations to analyze the effects of force and phosphorylation on filamin-A structure.
- Evaluated the structural changes and binding site accessibility under varying tensile forces and phosphorylation states.
Main Results:
- A tensile force of 40 pN partially relieves autoinhibition of the IgFLNa-R21 integrin binding site.
- Combined force and Ser(2152) phosphorylation completely dissociate autoinhibition with a reduced force requirement.
- Phosphorylation alone, without force, is insufficient to remove autoinhibition; force significantly lowers the threshold for beta-strand inhibitor removal.
Conclusions:
- Filamin-A functions as a tunable mechanosensor, with its sensitivity modulated by phosphorylation.
- Force and phosphorylation act synergistically to regulate filamin-A's interaction with the extracellular environment via integrins.
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