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A Common Binding Site for Actin-Binding Proteins on the Actin Surface


* Corresponding Author: Boston Biomedical Research Institute, 64 Grove Street, Watertown, Massachusetts 02472, U.S.A. Email:

The dynamic remodeling of the actin cytoskeleton plays an essential role in many cellular processes, including cell motility, cytokinesis, and intracellular transport. A large number of actin-binding proteins (ABPs) participate in this process, regulating the assembly of actin filaments into functional networks. ABPs are extremely diverse, both structurally and functionally, but they most seem to share a common binding area on the actin surface, consistent of the cleft between actin subdomains 1 and 3. Actin itself is thought to interact in this cleft in the filament. As a result, part of the cleft becomes buried in F-actin by inter-subunit contacts, whereas another part remains exposed and mediates the interactions of various filamentous actin-binding proteins. The convergence of actin-binding proteins into a common binding area imposes enormous constraints on their interactions and could serve a regulatory function. Because the cleft falls near the hinge for domain motions in actin, binding in this area is an effective way for ABPs to “sense” the conformation of actin, in particular conformational changes resulting from ATP hydrolysis by actin or from the G- to F-actin transition.


The dynamic remodeling of the actin cytoskeleton is essential for many cellular functions, including motility, cytokinesis, and the control of cell shape and polarity.1 Actin is the major component of the cytoskeleton. It exists in two different forms, a monomeric form (G-actin) and a filamentous form (F-actin). F-actin is structurally and functionally asymmetric, undergoing net association of ATP-actin monomers to the barbed end (+ end) and dissociation of ADP-actin monomers from the pointed end (- end), a process known as actin filament treadmilling. In vivo, the transition between G- and F-actin is tightly regulated by a vast number of actin-binding proteins (ABPs). These proteins direct the location, rate, and timing for actin assembly into different cytoskeletal networks such as filopodia, lamellipodia and focal adhesions.2-4 Typically, ABPs are multidomain proteins containing, in addition to their actin-binding domains, signaling domains and protein-protein interaction modules. Although the number of ABPs is extremely large and is constantly growing, the actin-binding domains of most ABPs can be grouped into structurally conserved folding families, including the WASP homology domain-2 (WH2),5 the actin-depolymerizing factor/cofilin (ADF/cofilin) domain,6 the gelsolin-homology domain,7 the calponin-homology (CH) domain,8 the formin homology 2 (FH2) domain9 and the myosin motor domain,10 to mention just a few. The structures of complexes of actin with some members of these folding families are now known, and are starting to reveal common features in the way ABPs interact with actin.11 Such common structural features and their functional implications are discussed here.

A Prevalent Target-Binding Cleft in Actin

From yeast to human, actin is one of the most highly conserved proteins in nature.12 It consists of 375 amino acids. The molecule is organized into two structurally related domains, which are thought to have resulted from gene duplication.13 The two domains can be further subdivided into subdomains 1 to 4 (Fig. 1A). Two diametrically opposed clefts separate the two large domains of actin. The larger cleft, between subdomains 2 and 4, constitutes the nucleotide-binding site, whereas the smaller cleft, between subdomains 1 and 3, mediates the interactions of actin with most ABPs (Fig. 1B).11 Thus, all the structures of complexes of actin with ABPs, except that of actin-DNase I,13 interact in this cleft (Fig. 2). Profilin also interacts to the back of this cleft in actin,14 although in a different way than most ABPs. The specifics of these interactions are discussed below.

Figure 1. A prevalent target-binding cleft in actin.

Figure 1

A prevalent target-binding cleft in actin. A) Ribbon representation illustrating the “conventional” view of actin. Two diametrically opposed clefts, the nucleotide cleft and the target-binding cleft, effectively separate the actin molecule (more...)

Figure 2. The cleft between actin subdomains 1 and 3 is a hot spot for actin-binding proteins.

Figure 2

The cleft between actin subdomains 1 and 3 is a hot spot for actin-binding proteins. A) Illustration of all the ABPs known to present and α-helix (shown in red) that interacts in the target-binding cleft in actin. An electrostatic surface representation (more...)


Gelsolin is a calcium regulated F-actin capping and severing protein.7 In the structure of the complex of gelsolin fragment 1 with actin,15,16 the major contact involves α-helix Ser 70-Asn 89 of gelsolin, which binds in the cleft between subdomains 1 and 3 of actin (Fig. 2). Actin residues Tyr 143, Ala 144, Gly 146, Thr 148, Gly 168, Ile 341, Ile 345, Leu 346, Leu 349, Thr 351, Met 355, and possibly the C-terminus of actin, which is typically disordered in the structures, line the cleft in actin. The interaction is mostly hydrophobic, although a few hydrogen bonds are also observed. The α-helix in gelsolin presents exposed hydrophobic side chains (Fig. 2), which interact with the hydrophobic amino acids that line the cleft in actin.

Vitamin D-Binding Protein (DBP)

A similar interaction was later observed in the structure of the complex of actin with DBP.17 Similar to gelsolin, DBP α-helix Ser194-Asp204 binds in the cleft in actin (Fig. 2). Although DBP interacts with actin over a large interface, the interaction involving this α-helix appears to play a predominant role in the formation of their complex. The presence of a common actin-binding motif in these two otherwise unrelated proteins was proposed to allow DBP to compete effectively for actin monomer binding, while freeing gelsolin for its severing function as part of the actin-scavenger system.17

Thymosin-β Domain

Thymosin-β4 is the prototypical member of the thymosin β family.4,18 Tβ4 is a small (5-kDa) actin monomer sequestering protein, which constitutes an important buffer of ATP-actin monomers in the cell. The actin-bound structures of a hybrid protein, consisting of gelsolin domain 1 and the C-terminal half of Tβ419 and that of the N-terminal half of ciboulot domain 1,20 a Tβ4-related molecule from Drosophila megalonaster, have been determined. The N-terminal portion of ciboulot and the C-terminal portion of Tβ4 from these two structures connect rather well to produce a model of the complex of Tβ-actin19 (Fig. 2). Combined, these structures reveal that the Tβ domain consists of two α-helices, an N- and a C-terminal α-helices, connected by a linker. The N- and a C-terminal α-helices cap the barbed and the pointed end of actin, respectively, providing a structural explanation for the monomer sequestering function of the Tβ domain. The N-terminal α-helix binds in the cleft between actin subdomains 1 and 3 (Fig. 2). The binding of the α-helix in ciboulot, however, differs from that of gelsolin and DBP in one important way. While the α-helix in ciboulot runs from back to front (according to the conventional view in (Fig. 1A), those in gelsolin and DBP run from front to back. A superimposition of the structures, using actin as a reference, reveals that despite the different directionalities of binding, some of the hydrophobic side chains in the α-helices of these three proteins occupy similar positions within the cleft in actin. Note, however, that there is no significant sequence similarity between the α-helices of these proteins. The only common feature is the periodicity of exposed hydrophobic amino acids on one side of the α-helix.

WASP Homology 2 (WH2) Domain

It had been proposed, based on sequence analysis, that the WH2 domain and the Tβ domain formed part of an extended family.5 However, this view remained controversial, in part because of the different biological functions and low sequence similarity between the two domains. 21 Moreover, Tβ proteins consist of one or multiple copies of the Tβ domain, whereas the WH2 domain is found within large multidomain proteins, typically in the form of tandem repeats. The recent determination of the structures of actin complexes with the WH2 domains of various cytoskeletal proteins, including the prototypical WH2 of WASP, confirmed to a large extent the proposed relationship.22 In particular, the WH2 domain presents and N-terminal α-helix whose hydrophobic side interacts in the cleft between actin subdomains 1 and 3. Here again, although there is no significant sequence conservation between the α-helices of Tβ and WH2, the periodicity of hydrophobic amino acids involved in the interaction with actin is well conserved. However, there are also important differences between the Tβ and WH2 domains. Notably, the WH2 domain lacks the C-terminal α-helix characteristic of the Tβ domain, which is consistent with the role of tandem WH2s in actin filament nucleation.22,23

Formin Homology 2 (FH2) Domain

Formins are a family of modular proteins that mediate the nucleation and elongation of unbranched actin filaments.9 The FH2 domain binds actin filament barbed ends and moves processively as the filaments elongate or depolymerize. The crystal structure of the FH2 domain of Bni1p in complex with actin has been determined recently.24 In the structure, FH2 forms a dimer, with each subunit interacting with two actin molecules in an orientation similar to that of the double-stranded barbed-end of the filament, consistent with the formation of a filament nucleus. Formin also turned out to have an α-helix that binds in the cleft between actin subdomains 1 and 3 (amino acids Ser 1422 to His 1434) (Fig. 2). The orientation of the α-helix in the complex with formin is similar to that of the WH2 and Tβ domains. Interestingly, the α-helix in formin only exposes a single hydrophobic amino acid (Ile 1431), with the rest of the interaction having a polar character.


Toxofilin is an actin sequestering protein from Toxoplasma gondii.25 This parasite displays a strikingly low amount of actin filaments, suggesting that actin monomer sequestration may play a key role in parasite actin dynamics. The structure of the complex toxofilin-actin is being determined in our lab. Strikingly, toxofilin also presents an α-helix, similar to that of the WH2 domain, that binds in the cleft in actin (Lee et al, in preparation).

Marine Toxins

Actin also binds a series of drugs and toxins, including cytochalasins, phallotoxins, macrrolide toxins and marine macrolide toxins.12 The structures of actin complexed with the marine toxins kabiramide C and jaspisamide A reveal that the binding site for these molecules is also the cleft between actin subdomains 1 and 3.26

Conformational Plasticity of the Target-Binding Cleft in Actin

The portion of the α-helix in ciboulot that interacts with actin is longer than in gelsolin and DBP. Ciboulot has exposed hydrophobic side chains along four consecutive helical turns (Fig. 2). These side chains bind in the hydrophobic cleft in actin, covering the entire length of the cleft. The N-terminus of the α-helix in ciboulot partially overlaps with the binding site of profilin,14 which binds to the back of the cleft in the standard view, although also interacting with subdomains 1 and 3. In contrast, Tβ4, whose α-helix is predicted to be shorter than that of ciboulot,27 can bind actin simultaneously with profilin.28 In gelsolin, DBP and formin, the portion of the α-helix that interacts with actin is even shorter, and binds only to the front half of the cleft. The orientation of the α-helices of gelsolin and DBP in the cleft is also opposite to that of formin, Tβ and WH2. Thus, the hydrophobic cleft in actin is long enough to accommodate interactions at its front or back halves, or throughout its entire length. This opens the possibility that two ABPs, whose binding sites on the cleft do not fully overlap, could bind to actin simultaneously, either transiently or as a stable complex. This appears to be the case for Tβ4 and profilin,28 as well as for certain WH2 domains and profilin (Chereau and Dominguez, J Struct Biol, in press). A similar situation can take place in the filament. Indeed, it is possible that in F-actin the D-loop of an actin subunit binds to the back of the hydrophobic cleft of a neighboring subunit, an interaction that can be in addition regulated by nucleotide hydrolysis by actin (Fig. 1C). This would explain how tandem WH2 domains can coexist with and nucleate actin filaments, as observed in spire.23 ABPs that bind at the front end of the cleft could either coexist with F-actin, compete with F-actin, or take advantage of nucleotide-dependent conformational changes in actin to access the cleft, possibly severing the filament. Coincidently, both Tβ429 and ADF/cofilin,30 which as proposed below may also bind in the cleft, change the twist of F-actin upon binding, suggesting competition with some of the inter-subunit contacts in F-actin. It appears therefore that the hydrophobic cleft in actin is highly adaptable, it can accommodate interactions with a range of unrelated ABPs. These interactions typically involve an α-helix in the ABP, but the general position and orientation of the α-helix varies. It also appears plausible that certain ABP could bind to different parts of the cleft simultaneously.

Crosstalk between the Target-Binding and Nucleotide Clefts

As explained above, the nucleotide cleft and the target-binding cleft effectively divide actin into two large domains (Fig. 1A). The polypeptide chain goes across domains only twice, and the point of intercept between the two domains constitutes the hinge for domain motions in actin, physically coinciding with the α-helix Ile136 to Gly14631,32 (Fig. 1A). In this way, nucleotide-dependent conformational changes in actin can be sensed by ABPs, explaining the strong correlation existing between the state of the nucleotide and the actin-binding affinities of most ABPs. The crosstalk between clefts is most likely also responsible for the inhibition of nucleotide hydrolysis resulting from the binding of many ABPs. Interestingly, a similar two-cleft system exists in myosin, where a hinge separates the nucleotide-binding cleft from the actin-binding cleft. In this way, nucleotide-dependent movements are physically transmitted to the actin-binding site, thereby modulating the actin-binding affinity of myosin.33

Implication for Other Actin-Binding Proteins

The evidence to date is consistent with the hydrophobic cleft in actin being a primary target for ABPs. Other proteins, whose binding sites on actin remain unknown, may also bind in this cleft. Any protein that binds in this cleft will most likely contain an α-helix, featuring few exposed and conserved hydrophobic amino acids, equivalent to those of gelsolin, DBP, WH2 and Tβ domains.


Such a conserved α-helix exists among members of the ADF/cofilin family.6 Although structures of various members of this family, including destrin,34 cofilin,35 actophorin,36 ADF1,37 and the N-terminal domain of twinfilin38 have been reported, a structure of a complex with actin has remained elusive. There is ample evidence linking ADF/cofilin helix 3 with actin binding.38-41 There is also a theoretical model of the actin-cofilin complex that takes into account the existing general structural similarity between cofilin and gelsolin and proposes a similar mode of binding for these two proteins.42 Because of the importance of ADF/cofilin helix 3 in actin binding,38-41 the fact that it is one of the most highly conserved regions in this family, and the presence of exposed hydrophobic side chains (Fig. 2B), it is plausible that ADF/cofilin α-helix 3 also binds in the hydrophobic cleft in actin (Fig. 2B). Due to the overall similarity between the ADF/cofilin37 and gelsolin7 folds, it is further possible that the directionality of binding of ADF/cofilin α-helix 3 is the same as in gelsolin and DBP, i.e., from front to back.


The hydrophobic cleft also appears to be involved in inter-subunit contacts in F-actin,43 raising the exciting possibility that ABPs compete with actin for this binding site. This may require the presence of an α-helix, containing exposed hydrophobic side chains within actin itself. Moreover, changes to this α-helix or the hydrophobic cleft would be expected to affect actin assembly. Consistent with this idea, proteins that are known to bind in the cleft often block actin polymerization. Moreover, actin labeled at Cys 374 with tetramethylrhodamine-5-maleimide (TMR) becomes polymerization deficient, allowing TMR-actin to be crystallized in the absence of any bound protein.44 The resulting structure reveals the TMR probe partially blocking the cleft in actin, which could explain the dramatic effect that this probe has in polymerization. The most likely candidate to bind in the hydrophobic cleft in F-actin is the DNase I-binding loop (D-loop, amino acids His 40-Gly 48) of a neighboring actin subunit (Fig. 2C). As its name indicates, the D-loop mediates the formation of the strong actin-DNase I complex.13 Labeling45 or cleavage46,47 of the D-loop affects actin polymerization. Furthermore, the D-loop can be directly cross-linked to Cys 374 in the cleft of an adjacent monomer within an F-actin strand.48,49 Therefore, the existing evidence suggests that in F-actin the D-loop of an actin monomer binds in the hydrophobic cleft of a neighboring monomer. However, in most actin structures the D-loop appears either disordered or folded as an extended β-hairpin loop, not an α-helix. Interestingly, in one of the structures, that of TMR-actin in the ADP state, the D-loop adopts an α-helical conformation.44 The α-helix in the D-loop, which had not been observed before, was assumed to be part of the global nucleotide-dependent conformational change.32,44 However, it is also possible that this conformation is only stable if the D-loop is in contact with a binding partner (or a neighboring molecule in the crystal as it is the case in this structure). Thus, this structure may have provided the first glance of the structure of the D-loop in the filament, where its conformation may be constrained by inter-subunit interactions, which could favor the α-helical conformation. Independent of these considerations, an updated model of the actin filaments has been proposed that positions the loop, in the α-helical conformation observed in the ADP-TMR-actin structure, in close proximity of the cleft of the next subunit in the filament strand.50 The presence of the D-loop at this location would result in steric hindrance with TMR bound at Cys 374, possibly explaining the negative effect that this probe has on polymerization.

EM reconstructions of F-actin decorated with various actin-binding proteins, including myosin,50, 51 cofilin,30 and the ABD domains of various members of the spectrin family,52-56 all show density masking the cleft in F-actin.57 It is therefore likely that these proteins all present specific interactions with the cleft in actin. Because actin, and the hydrophobic pocket in particular, are highly conserved from yeast to human, a potentially powerful way to determine the corresponding binding interface of F-actin-binding partners is to plot sequence conservation on the surface of high-resolution structures. Proteins typically tolerate significant sequence variation on their surface, but the F-actin binding function would be expected to force sequence conservation at the binding interface.


Supported by NIH grant GM073791. The author thanks Francois Ferron for help with the preparation of Figure 1.


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