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Boomerangs, Bananas and Blimps: Structure and Function of F-BAR Domains in the Context of the BAR Domain Superfamily

, ,* and .

* Corresponding Author: Vinzenz M. Unger and Pietro De Camilli—Departments of Molecular Biophysics and Biochemistry and Interdepartmental Neuroscience Program, Yale University School of Medicine, New Haven, CT 06510, USA. Email:ude.elay@tsorf.mada

The Pombe Cdc15 Homology Proteins, edited by Pontus Aspenström.
© 2008 Landes Bioscience.
Read this chapter in the Madame Curie Bioscience Database here.

Proteins that belong to the BAR (Bin, Amphiphysin, RVS) domain superfamily are alpha-helical bilayer-binding modules that have evolved to induce or stabilize membrane curvature during cellular events like endocytosis, cell division and organelle biogenesis. Within the superfamily, a subset of proteins possessing F-BAR (Fes/CIP4 homology-BAR) domains play key roles in membrane remodeling and loss-of-function mutations in genes coding for F-BAR proteins are associated with human diseases. Here, we review how F-BAR domains compare structurally with related members of the BAR domain superfamily and discuss the proposed mechanisms underlying their membrane-molding activity and regulation. We end by highlighting the functional properties of select F-BAR domains that were elucidated by electron cryo-microscopy and 3D reconstruction of these modules while bound to flat and curved membranes.

Introduction

Life exists within the boundary of cellular membranes. The assembly of amphipathic lipids into fluid bilayers that are impermeable to macromolecules is fundamental to the existence of all living organisms. At the same time, this partitioning poses problems since the vital processes of cell division, migration, endo-, exo- and transcytosis all require cells to remodel and even break their membranes without opening damaging or lethal leaks. Evolutionary forces have therefore fashioned protein modules that can reversibly mold membranes into planar, spherical, cylindrical and saddle-shaped surfaces.1 Members of the BAR (Bin, Amphiphysin, RVS) domain superfamily of proteins are recruited from the cytoplasm to induce or stabilize states of high membrane curvature in response to regulatory signals. 2 Within the BAR domain superfamily, a unique subset of proteins that possess F-BAR (Fes/CIP4 homology-BAR) domains have been shown to play key roles in membrane and cytoskeletal remodeling, coupling these processes by simultaneously bending bilayers and triggering the polymerization of actin fibers. 3 , 4 Proteins of the F-BAR subset are also notable for being associated with metabolic, inflammatory, neurological and malignant diseases. 3 , 5 Here, we review how F-BARs compare structurally within the BAR domain superfamily and the proposed mechanisms by which they mold membranes. Finally, we highlight some functional properties of select F-BAR modules that were recently discovered through direct visualizations of these domains bound to model membranes.

The General Signature of the BAR Domain Superfamily

With more than 14 near-atomic structures of BAR domains, we can begin generalizing about their form, function and evolutionary history 6 - 18 (Fig. 1). The first structure solved, residues 118-341 of human arfaptin-2, was not immediately recognized as the founding member of the BAR domain family. 8 Arfaptin's ability to induce membrane-curvature was not discovered until the second structure, residues 26-242 of drosophila amphiphysin—a protein known to bend membranes into narrow tubules 19 —was shown to be arfaptin's structural homolog and their common quaternary fold was proposed to be “a universal and minimal BAR domain…a dimerization, membrane-binding and curvature-sensing module”. 9 The shared features of these two structures have proven to be defining elements of the BAR superfamily: monomers with three alpha-helices arranged in anti-parallel coiled-coils that dimerize to form curved modules with a positively-charged surface. Like the three-helix bundles of the spectrin superfamily, 20 a regular spacing between hydrophobic residues at every third or fourth position appears to drive the assembly of BAR monomers into coiled-coils. 21 , 22 The dimerization interface between BAR monomers is composed of mixed hydrophobic and polar surfaces that are buried where stretches of the alpha-helices from one monomer pack against those of the other monomer in an anti-parallel orientation (Fig. 1). The surface area involved in dimerization varies more than 2-fold from ∼2200 to ∼4800 square angstroms between individual structures and a major unanswered question is whether most BARs form constitutive dimers or whether dimerization can be a regulated event that occurs in the cytosol or on the membrane surface. 10 - 12 , 17 , 18 While many interesting differences exist between individual BAR modules, architectural conservation of the dimeric 6-helix bundle is the touchstone of the BAR domain superfamily.

Figure 1. Comparative views of representative members of the BAR domain superfamily.

Figure 1

Comparative views of representative members of the BAR domain superfamily. One monomer of each BAR domain is shown in blue or orange. Conjoined PH and PX domains are shown in green. In the case of the N-BAR domain from endophilin, the position and orientation (more...)

Diverse Membrane-Molding Mechanisms

Shifting our focus from the conserved 6-helix bundle to the unique features of known structures, the distinctive adaptations of individual domains become apparent and some concepts about the mechanisms by which BARs mold membranes suggest themselves. In particular, the still open question about whether BARs sense, stabilize or induce membrane curvature will be considered for different members of the superfamily. Namely, a given protein module will induce curvature when the difference in the free energy of binding to a curved versus a flat membrane exceeds the free energy required for membrane deformation. In cases in which the difference between binding energies is less than that required for deformation for a given membrane, a protein module may still bind with higher affinity to a membrane that is already curved, i.e., it will detect or sense a degree of curvature that matches its own shape. During the discussion of each of the subsets within the superfamily, four themes will be encountered that will help explain their properties as curvature sensors or generators: overall shape, the presence of conjoined domains or moieties, oligomerization states and known binding partners.

Classical BAR and N-BAR Domains

The BAR domain of arfaptin serves as the founding and paradigmatic example of a classical banana-shaped BAR module, characterized by a concave surface with positive charges aligned to interact with the negative charges of the membrane 8 (Fig. 1). Closely related to arfaptin in their overall degree of curvature, the BARs of amphiphysin and endophilin are also banana-shaped and have a similar arrangement of positive charges along their concave surfaces. 6 , 7 , 9 , 11 , 13 Just looking at these structures leads one to the “scaffolding” hypothesis, which posits that these BAR modules mold membranes by directly imposing their charged, curved shapes via electrostatic attraction. 2 , 9 Complicating the question about whether such molecular-scale scaffolding by the BAR itself induces or detects curvature, the BARs of endophilin and amphiphysin are conjoined with N-terminal sequences of ∼26 residues that appear to fold into alpha-helices (helix-0) in the membrane's interfacial environment. 11 , 23 The intercalation of this amphipathic moiety into one leaflet of the bilayer has been proposed to act like a “wedge” that causes local buckling when the polar headgroups of one monolayer are pushed apart. 1 Peter et al dubbed the combination of a BAR plus an N-terminal amphipathic helix the N-BAR module and such proteins appear to constitute a discrete phylogenetic subset of the BAR domain superfamily. 9 , 24

Biochemical 10 , 23 and spectroscopic 11 data indicate that the N-terminal helices of endophilin and amphiphyisn do insert into one membrane leaflet, such that the midpoint of the helix is at the level of the phosphate of the lipid headgroups. 11 This shallow insertion has been proposed to be the primary driving force for inducing curvature de novo, 9 , 23 while the BAR module itself has been proposed to simply stabilize the resulting curvature. 9 - 11 In support of this wedge-insertion theory, curvature-generating proteins that do not have an intrinsically-curved shape (e.g., Epsin and Sar1 proteins) can induce membrane curvature with amphipathic helices alone. 25 , 26 Yet there have been studies in which amphipathic helices were shown to sense pre-existing curvature without inducing curvature de novo. 27 What is more, in vitro experiments have shown that the arfaptin BAR—which lacks a conjoined amphipathic helix—can transform liposomes into narrow membrane tubules in vitro as efficiently as the epsin1 ENTH domain or the N-BAR of amphiphysin. 9 Moreover, amphiphysin and endophilin constructs that lack helix-0 can still tubulate liposomes in vitro, albeit at higher protein concentrations. 9 Thus, it remains unclear whether amphipathic wedges or shape-based scaffolds drive curvature induction versus curvature sensing for these members of the BAR domain superfamily.

While there are no known interactions between the BAR domains of endophilin or amphiphysin with regulatory proteins, arfaptin's BAR was not initially characterized as a membrane-associated scaffold but as an Arf-regulated binding platform for the Rac family of small GTPases. 8 Along with the elucidation of its structure, arfaptin's BAR domain was shown to bind and sequester nucleotide-bound Rac via its concave face, while activated Arf:GTP was shown to bind with higher affinity to an unknown site on the BAR domain and to displace Rac 8 (Fig. 1). These observations were used to rationalize the observed requirement of Arf for Rac-mediated membrane ruffling, 28 though it may be that displacing Rac from the concave surface of the BAR domain frees it to interact with the membrane and that arfaptin is at least partially responsible for shaping the plasma membrane in response to these signaling events.

BAR-PH and PX-BAR Domains

Like the N-BAR domains described above, other BAR domain superfamily modules have co-evolved with conjoined lipid-binding motifs, including PH (Plecksrin Homology) and PX (PhoX Homology) domains. Structural examples of these conjunctions include the BAR-PH module of APPL-1 16 , 17 and the PX-BAR module of SNX9. 18 In the case of the BAR-PH structure, an acute angle of dimerization produces one of the most highly-curved “boomerang” shapes of the known BAR structures. This geometry positions the phospholipid binding site of the PH domain (found at the dimers twin-tips) in line with the membrane-binding surface of the BAR domain, strongly suggesting that the conjoined domains act together to recognize specific phosphorylated inositides while scaffolding a very high degree of membrane curvature (Fig. 1).

The hybrid PX-BAR structure of SNX9 is distinctly different, in that the N-terminal PX domain appears to be flexibly coupled to the lateral surface of the BAR by a split “yoke” sub-domain 18 (Fig. 1). Despite the conservation in the core BAR fold, the curvature of BAR dimers results from both the angle at which the monomers dimerize and from the kinks in individual helices. 6 , 9 , 13 , 18 In the SNX9 PX-BAR, alpha-1 is kinked almost exactly in the middle and this kink bends the helix in the opposite direction as the main curvature of the BAR dimmer. 18 Hence, while the BAR-PH structure is one of the most strongly-curved BAR solved to date, the PX-BAR exhibits a relatively moderate radius of curvature that would fit a circle of diameter ∼40 nm, 18 in comparison with ∼17 nm for the BAR-PH of APPL-1. 16 , 17 Despite this difference, electron micrographs of tubules generated by purified PX-BAR domains are ∼20 nm in diameter, comparable to tubules generated by N-BAR domains. 19 , 23 In addition, an amphipathic sequence found immediately N-terminal to the PX-BAR domain appears to be required for tubulation in vitro and in living cells 18 while no such sequence exists within or flanking BAR-PH domains. 16

Returning to the theme of interactions with small GTPases, APPL-1 and APPL-2 have been shown to bind Rab5 and Rab21 via the BAR portion of their N-terminal BAR-PH domain. 16 , 29 These APPL proteins associate specifically with activated Rab5/21:GTP and upon epidermal growth factor (EGF) stimulation, the EGF receptor is trafficked through APPL-positive endosomes. GTP hydrolysis is required to release APPLs from these endosomes. 29 , 30 Unlike the binding of Rac to the concave surface of the arfaptin BAR, a mutagenesis and immunoprecipitation analysis suggests that the binding site for Rab5 and Rab21 is found on the convex surface of the module, in the angle between the PH and BAR domains. 16 Determining the precise structural basis for these observations would yield important insights into why membrane binding by APPLs depends on Rab5/21 and could illuminate how cells regulate this endosomal pathway.

I-BAR Domains

Though only distantly homologous with classical BARS in primary sequence, I-BAR (Inverse-BAR) domains are also descendents of an elongated, dimeric six-helix bundle and are characterized by a surface with positive charges aligned to interact with the negative charges of the membrane. 14 , 15 , 30 , 31 However, I-BARs are found in a family of proteins that includes IRSp53 (Insulin Receptor Substrate) and MIM (Missing-In-Metastasis; or IMD for IRSp53, MIM homology Domain) and—having nearly neutral curvature—have been described as “zeppelin” shaped. 32 The moniker I-BAR is particularly appropriate because these domains were proposed to induce the formation of filopodia or plasma membrane extensions through an inverse scaffolding mechanism that generates negative membrane curvature, protrusions rather than invaginations, through imposition of the dimer's convex and cationic surface. 14 Consistent with the observation that these proteins induce negative curvature, no amphipathic “wedge” sequences have been identified within or flanking the I-BAR modules described to date. Finally, at least one I-BAR domain directly binds to the small GTPase Rac and this relationship regulates filopodia formation 30 , 32 , 33 (Fig. 1).

F-BAR Domains

F-BAR domains are the most recently adopted members of the BAR superfamily and were found via sequence searches for regions of low sequence homology to BAR domains but with secondary structure predictions consistent with three-helix, anti-parallel coiled-coils. 9 , 34 An entire family of actin-regulatory proteins with such homology were already known as PCH (S. pombe Cdc15 Homology) proteins, 3 , 35 or FCH (Fes and CIP4 Homology) proteins plus a CC (Coiled-Coil) domain 4 , 36 or EFC (Extended FCH) domains. 12 , 37 Extensive biochemical and cell biological analyses support the hypothesis that these regions are functional and structural relatives of the BAR domain 12 , 34 , 37 and the name F-BAR (FCH-BAR) was accordingly proposed. 34 Structures solved by Shimada et al and Henne et al validated this hypothesis, providing structural, spectroscopic and biochemical evidence that the F-BAR modules of FBP17, CIP4 and FCHo2 are alpha-helical, anti-parallel dimers with a conserved 6-helix bundle core, but with arc depths ∼3-fold smaller than those of “classical” BARs 10 , 12 (Fig. 1). The more subtle curvature correlates directly with the larger diameter membrane tubules formed by F-BAR versus N-BAR domains in vitro 10 , 12 , 34 and in living cells 38 (Figs. 1 and 2).

Figure 2. Membrane tubulation as seen by fluorescent imaging of a cell expressing GFP-FBP17 (bar = 10 microns), by thin-section EM of a similar cell (bar = 100 nm) and by iterative helical single particle reconstruction of an F-BAR induced membrane tubule (bar = 20 nm).

Figure 2

Membrane tubulation as seen by fluorescent imaging of a cell expressing GFP-FBP17 (bar = 10 microns), by thin-section EM of a similar cell (bar = 100 nm) and by iterative helical single particle reconstruction of an F-BAR induced membrane tubule (bar (more...)

F-BARs are also unique in that they possess two very short alpha helices that are N- and C-terminal to the canonical three-helix bundle constituting the monomeric unit. The N-terminal alpha-1 of one monomer interacts with the C-terminal alpha-5 of the adjacent monomer, contributing to dimer formation. Furthermore, F-BAR monomers have “an extended C-terminal peptide” that interacts with alpha-3 and alpha-4 of the adjacent monomer, all together doubling the surface area buried by dimerization in comparison with classical BAR domains. 10 , 12 Accordingly, Shimada et al find that the F-BAR domains of human CIP4 and FBP17 are constitutive dimers, whereas Henne et al report that after deleting the extended c-terminal peptide FCHo2 dimers become relatively weak, with a Kd on the order of dissociation constants reported by the McMahon group for other “classical” BAR domains (∼2.5 micromolar versus 2-15 micromolar; Henne et al, 2007; Gallop et al, 2006). Biologically, this suggests that the extended C-terminal peptide is an important functional component of the F-BAR domain and highlights open questions about whether dimerization is a regulated step for select members of the superfamily.

Beyond its role in dimerization, the C-terminal extended peptide has recently proven to be a critical component of F-BAR function through its role in mediating higher-order oligomerization and cylindrical coat formation. 38 The hypothesis that members of the BAR domain superfamily can form higher-order oligomers on the membrane surface was first suggested by electron micrographs of tubules formed by amphiphysin and endophilin BAR domains with an arrangement of thin rings, arcs or spirals around their circumference. 19 , 23 Subsequently, bi-functional chemical cross-linkers produced large aggregates when applied to similar in vitro preparations. 9 , 39 Finally, Shimada et al reported that purified F-BAR domains also induced tubular membranes that appeared to be encased by a tightly-wound thread of protein oligomers, which they proposed were strings of F-BARs held together by a unique tip-to-tip contact observed in their crystal structures (Shimada et al 2007).

Taken together, these observations constituted an important line of investigation that addresses the sometimes overlooked fact that if an individual BAR can generate (rather than sense) membrane curvature, this curvature will only be local and limited to a spatial scale on the order of the domain itself. 40 In contrast, transformations in membrane shape like those observed during endocytosis or the elongation of tubules must require the concerted effort of many proteins acting in close spatial and temporal proximity. In light of this, biologically meaningful membrane deformations likely require the formation of protein coats to shape or stabilize the underlying membrane, presumably through direct interactions between individual protomers. Theoretical considerations have also suggested the possibility that in the absence of protein-protein interactions, protein-induced changes in bilayer properties may create attractive forces that cause microscopically bent bilayer regions to coalesce into macroscopic curvature domains. 41 - 43 The kinetics of coat-formation through direct protomer interactions are likely to differ significantly from those of indirect coalescence of curved membrane regions and this may be an important difference between BARs that induce curvature de novo and BARs that only sense or stabilize curvature generated by other proteins. Developing quantitative models and rigorous experimental tests of both the physical mechanisms and the biological significance of curvature induction versus curvature sensing through these mechanisms is an exciting area of ongoing research.

Membrane-Bound F-BARs Form a Coat Composed of Shape-Based Scaffolds

Efforts to refine the mechanistic understanding of membrane remodeling by the BAR domain superfamily have been enhanced by electron microscopic studies directed at visualizing how F-BARs interact with the bilayer and with each other. 38 Specifically, these studies exploited the unique ability of electron cryomicroscopy (cryo-EM) techniques to allow observation of samples under hydrated, near-native conditions where the structure and arrangement of membrane-associated and membrane-embedded proteins are fully preserved. When combined with digital image analysis for the alignment and averaging of different 2D projections, 3D reconstructions can be built to extract and interpret macromolecular information that is inaccessible to other structural methods. In addition, combining lower resolution reconstructions derived from cryo-EM with computationally-docked high-resolution crystal/NMR structures can lead to detailed views that span the spectrum from atoms to sub-cellular membranous organelles (Fig. 2).

Recently, a first study focused on the F-BAR modules found at the N-terminus of proteins from the Toca family (transducer of Cdc42-dependent actin assembly), namely Toca-3/CIP4 and Toca-2/FBP17, 44 whose crystal structures have been solved. 12 By fitting the atomic models of these F-BARs into 3D reconstructions of membrane tubules generated in vitro and observed by cryo-EM, it was possible to observe directly how F-BARs employ a combination of scaffolding and collective coat formation to induce curvature. 38 Specifically, the scaffolding hypothesis predicts that there should be resolvable points of contact between the phospholipid headgroups and clusters of cationic residues found on the concave face of the F-BAR module and that these contacts will constrain the membrane to match the curvature of the domain. Essentially proving this model, the reconstructions clearly resolved how four clusters of Lys and Arg residues on the surface of the F-BAR dimer mediate the attractive forces that enable these rigid dimers to impose their own shape on the underlying bilayer. Moreover, the molecular-scale scaffolding by individual F-BARs was amplified around and along the tubule by the self-assembly of a unique helical coat, held together by tip-to-tip and extensive lateral interactions. The broad, overlapping lateral interaction involved ∼50% of the dimer's lateral surface, including the entire C-terminal extended peptide. Notably, these or similar contacts were not observed in any of the solved crystal structures, emphasizing the unique advantages of analyzing molecular scaffolding in the presence of the lipid bilayer substrate. Fitting of near-atomic crystal structures into the cryo-EM maps further suggested that specific contacts are important for the formation of the lateral interactions, including ionic and hydrophobic interactions between surface-exposed residues that have been conserved throughout the evolutionary history of the Toca proteins. Experimental verification of the functional importance of the residues participating in these lateral interactions through fluorescent imaging of mutated F-BAR proteins in living cells demonstrated the predictive value of the hybrid model and set the stage for more detailed structure-function studies.

A simple visual inspection of the twisted or “tilde” shape of the FCHo2 F-BAR module 10 suggests that these F-BARs may also use lateral interactions for the formation of organized coats (Fig. 1). Similarly, it is possible that other modules of the BAR domain superfamily oligomerize into coats with specific architecture, whether through tip-to-tip and/or lateral interactions. If this proves to be the case, polymerization properties could provide a simple yet efficient mechanism that enables different members of the BAR domain superfamily to distinguish self-similar domains during membrane remodeling. Consistent with this idea, we observed that F-BAR and N-BAR proteins dynamically segregate from each other on membrane surfaces during membrane remodeling 38 both in vitro and in living cells. Such segregation may be determined in part by the affinity of a given BAR for a specific degree of curvature, but stereotyped protein-protein interactions may further endow different BARs with the ability to recruit self-similar modules to form discrete membrane microdomains that are enriched for certain lipid and trans-membrane protein cargoes.

Returning to the role of amphipathic “wedges”, no such sequences have been identified within or flanking the F-BAR modules of Toca proteins and there was no evidence at the resolution of the cryo-EM analysis of amphipathic alpha-helices being intercalated into one leaflet of the bilayer. This is noteworthy in light of the discussion above on whether BARs sense, stabilize or induce membrane curvature, as it appears that F-BARs of the Toca family can generate curvature de novo with no apparent contribution from amphipathic insertions. Yet, the cryo-EM studies did suggest that the membrane-bending energy and the energy liberated by membrane-binding of F-BAR scaffolds are on the same order of magnitude, in that simple manipulations of the temperature or varying the lipid composition could divorce membrane-binding from membrane-bending. For example, lowering the temperature below the Tm of the principal lipid species (palmitoyl-oleyl phosphatidyl-serine, POPS)—a manipulation which presumably increased the rigidity of the membrane—inhibited tubule formation. F-BAR modules of the Toca family still avidly bound to these chilled membranes and formed oligomeric arrays in which laterally-adjacent dimers aligned in register while still forming the tip-to-tip contacts seen in the helical lattice. In this state, the modules were lying on their sides and thus could not directly impose their concave faces on the membrane or form the lateral interactions required for helical coat assembly. Warming these membranes above their Tm to decrease the membrane-bending energy enabled the membrane to adopt the intrinsic curvature of the F-BAR's concave surface and the flat membrane sheets were transformed into tubules. In the case of these F-BARs, there is no obvious reason to invoke membrane curvature-mediated attractive forces since these dimers interact directly and extensively with each other on the surface of both flat and curved membranes. It may be that these F-BAR modules have evolved to cluster together in limited oligomeric arrays on the surface of the plasma membrane, ready to induce tubule formation in response to regulatory signals mediated by small GTPases.

The Shape of Things to Come

Remaining questions include the means by which cells regulate BAR domain function in time and space, targeting them to the appropriate membranes at the required times. For example, the current understanding of the mechanism of dimerization suggests that posttranslational modifications or binding partners could inhibit the formation of the 6-helix bundle that defines the BAR fold. 11 Similar mechanisms may be employed to regulate membrane-binding. As noted earlier, BAR domains appear to nonspecifically bind anionic lipid headgroups, but synergistic partnerships with lipid flanking modules that bind lipids, such as PH and PX domains, are thought to contribute to membrane targeting of some BAR proteins. Simple clusters of four or more K/R residues, like those found in BAR domains or in regions that flank BAR domains, 45 have been shown in vivo to specifically interact with PI(3,4,5)P3 and PI(4,5)P2. 46 The nonspecific interactions with anionic headgroups see in vitro with liposome preparations may not be comparable with in vivo conditions—especially given that electrostatics are sensitive to solution ionic strength and pH, equilibrium conditions in vitro which are unlikely to adequately mimic the cystol-membrane interface. Other means of regulation may come into play for each step of higher-order oligomerization reactions, whether of helical coats or of discrete rings. Small GTPases, which typically cooperate with phosphoinositides to control specificity of membrane interactions 47 are likely to play a critical role, as suggested by the described interactions between BAR proteins and GTPases. 30 This general regulatory scheme is suggested by the cases of arfaptin, IRSp53 and APPL proteins, where the binding of small GTPases to the BAR domain may block or facilitate membrane binding. 8 , 16 , 32 , 33 Other binding partners or posttranslation modifications may be identified that specifically prevent the formation of promiscuous coat interactions between BAR modules at inappropriate times. There is also a great deal of interest and much to be learned about the interplay between actin fiber polymerization and BAR-mediated membrane deformation, in which there are likely to be many levels of coordination underlying processes like endocytosis or filopodia formation. Finally, the precise physiological roles of most members of the BAR domain superfamily remain to be unraveled.

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