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Published online
doi:10.1083/jcb.200707073
The Journal of Cell Biology, Vol. 179, No. 5, 1011-1025
The Rockefeller University Press, 0021-9525 $30.00
© Nakamura et al.
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Article

Structural basis of filamin A functions



Fumihiko Nakamura1, Teresia M. Osborn1,2, Christopher A. Hartemink1, John H. Hartwig1, and Thomas P. Stossel1

1 Translational Medicine Division, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115
2 Department of Rheumatology and Inflammation Research, Göteborg University, Gothenburg, Sweden

Correspondence to Fumihiko Nakamura: fnakamura{at}rics.bwh.harvard.edu

Filamin A (FLNa) can effect orthogonal branching of F-actin and bind many cellular constituents. FLNa dimeric subunits have N-terminal spectrin family F-actin binding domains (ABDs) and an elongated flexible segment of 24 immunoglobulin (Ig) repeats. We generated a library of FLNa fragments to examine their F-actin binding to define the structural properties of FLNa that enable its various functions. We find that Ig repeats 9–15 contain an F-actin–binding domain necessary for high avidity F-actin binding. Ig repeats 16–24, where most FLNa-binding partners interact, do not bind F-actin, and thus F-actin does not compete with Ig repeat 23 ligand, FilGAP. Ig repeats 16–24 have a compact structure that suggests their unfolding may accommodate pre-stress–mediated stiffening of F-actin networks, partner binding, mechanosensing, and mechanoprotection properties of FLNa. Our results also establish the orientation of FLNa dimers in F-actin branching. Dimerization, mediated by FLNa Ig repeat 24, accounts for rigid high-angle FLNa/F-actin branching resistant to bending by thermal forces, and high avidity F-actin binding and cross-linking.

F. Nakamura and T. M. Osborn contributed equally to this paper.

Abbreviations used in this paper: ABD, actin-binding domain; C-T, carboxy terminal; FLNa, filamin A; IgFLNa, immunoglobulin-like filamin A domain; Kapp, apparent dissociation constant: N-T, amino terminal.


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