The dynamic remodeling of actin filaments (F-actin) concentrated at the cell periphery is responsible for cell translocation, for cell shape changes, and for cellular resistance to potentially disruptive mechanical stresses. These mechanical tasks depend in large measure on the coherence of three-dimensional (3D) F-actin gel networks (Discher et al., 2005), and cross-linking agents confer this coherence on intracellular F-actin (Matsudaira, 1994). The most potent among many F-actin cross-linking agents is the first recognized nonmuscle F-actin-binding protein, now known as filamin A (FLNa). FLNa expression is essential for mammalian development (Feng et al., 2006; Ferland et al., 2006; Hart et al., 2006) and even small FLNa deletions or point mutations lead to diverse congenital anomalies (Robertson et al., 2003; Robertson, 2005; Kyndt et al., 2007). Cultured cells lacking FLNa protein expression exhibit unstable surfaces, are incapable of locomotion, and have impaired mechanical resistance (Flanagan et al., 2001; Kainulainen et al., 2002). FLNa confers elastic properties on F-actin networks subjected to prestress in vitro, and the network rigidities achieved simulate values observed for prestressed living cells (Gardel et al., 2006). The power of FLNa as an F-actin gelation promoter resides in its efficiency in recruiting F-actin into extended networks, and the source of this efficiency is its ability to orient each cross-linked rod-like actin filament at right angles, there by minimizing redundant cross-linking (Hartwig et al., 1980; Hartwig and Shevlin, 1986). In addition, the mechanical properties of F-actin/FLNa networks depend on FLNa’s capacity to cross-link F-actin with high avidity while permitting sufficient interfilament flexibility for networks to exhibit fully reversible elastic deformation in response to high stresses without rupturing (Gardel et al., 2006).

FLNa also binds numerous cellular components other than F-actin, including membrane receptors, enzymes, channels, signaling intermediates, and transcription factors, and it modulates the functional activities of these binding partners (Stossel et al., 2001; Feng and Walsh, 2004; Popowicz et al., 2006). Because many of these binding partners regulate actin assembly and disassembly, FLNa resides at the center of a complex feedback system in which signaling around it organizes actin architecture that, in turn, regulates signaling. A comprehension of the fine structure of FLNa is essential to understand how this molecule can execute diverse and complex functions and to relate specific arrangements of these functions to a growing catalogue of biological and clinical abnormalities ascribable to FLNa. FLNa is a homodimer with conserved F-actin–binding domains (ABDs) consisting of two calponin homology (CH) sequences (CH1 & CH2) at the amino termini (NT) of its 280.7-kD, 80-nm-long subunits. The amino acid sequence of FLNa’s ABD is representative of ABDs of the α-actinin or spectrin superfamily (Hartwig, 1995), with the exception that the FLNa ABD has a