Bar domain proteins: a role in tubulation, scission and actin assembly in clathrin-mediated endocytosis

doi:10.1016/j.tcb.2006.08.004

Trends in Cell Biology

Volume 16, Issue 10, October 2006, Pages 493-498

https://doi.org/10.1016/j.tcb.2006.08.004 Get rights and content

Endocytosis is an important way for cells to take up liquids and particles from their environment. It requires membrane bending to be coupled with membrane fission, and the actin cytoskeleton has an active role in membrane remodelling. Here, we review recent research into the function of Bin–Amphiphysin–Rvs (BAR) domain proteins, which can sense membrane curvature and recruit actin to membranes. BAR proteins interact with the endocytic and cytoskeletal machinery, including the GTPase dynamin (which mediates vesicle fission), N-WASP (an Arp2/3 complex regulator) and synaptojanin (a phosphoinositide phosphatase). We describe three classes of BAR domains, BAR, N-BAR and F-BAR, providing examples of each discussing and how they function in linking membranes to the actin cytoskeleton in endocytosis.

Section snippets

The actin cytoskeleton facilitates endocytosis

Endocytosis is crucial in many cellular processes, including receptor recycling and degradation, delivery of membrane-bound and soluble cargo to intracellular organelles, and nutrient uptake. Mammalian cells have at least five endocytic pathways: clathrin-dependent; caveolae-dependent; clathrin- and caveolae-independent; macropinocytosis; and phagocytosis 1, 2. Clathrin-dependent endocytosis is probably the most thoroughly studied of these processes and is important for the recycling of

The actin cytoskeleton is modular

The actin cytoskeleton is a highly dynamic network of more than 100 regulatory and structural proteins that enable cells to form and remodel structures such as filopodia, lamellipodia, adhesions, phagosomes and endocytic vesicles. Actin interfaces not only with the plasma membrane, but also with internal membranes, such as the Golgi complex [10] and endocytic vesicles [3]. Actin polymerization generates force by pushing against membranes through a linker protein (or proteins) that recruits

The Arp2/3 complex and the Diaphanous-related formins act as actin filament-generating machines

Assembly of new actin filaments is tightly regulated in cells, to enable cells to respond rapidly to stimuli and to assemble specialized actin structures only when and where they are required. The main activators of new filament assembly are Arp2/3 complex, a seven-protein complex containing two actin-related proteins and the Diaphanous-related formins (DRFs; for a review see Ref. [11]). The Arp2/3 complex and the DRFs are both activated by Rho-family small GTPases, which are guanine

The actin cytoskeleton deforms and moves membranes

Lipid membrane remodelling is required for endocytic events [13]; vesicles must invaginate before they are pinched off a membrane and released into the cytoplasm. Actin filaments probably have multiple active roles in deforming and moving membranes during endocytic trafficking. Actin filaments adjacent to membrane surfaces can act as a scaffold to assemble the proteins needed to drive membrane events. Polymerization of actin can be inhibitory to dynamin-induced budding of vesicles [14], so

BAR domain proteins are important linkers between membranes and the cytoskeleton

The BAR domain is emerging as one of the main links between membranes and the actin cytoskeleton. The BAR domain is highly conserved across evolution and is found in numerous proteins that have a role in membrane dynamics (Table 1). The crystal structures of the N-BAR domains of amphiphysin and endophilin (see later) recently revealed that the BAR domain is a banana-shaped α-helical dimer that functions to sense highly curved membranes 15, 16, 17, 18. The banana shape of the BAR domain favours

BAR domain proteins in endocytosis

BAR proteins are diverse in sequence and organization but have in common that they are usually found at sites of dynamic membrane remodelling, and a subclass of BAR proteins has been linked to endocytosis (Table 1; http://www2.mrc-lmb.cam.ac.uk/NB/McMahon_H/group/BARdomains/BARs.html). A common feature of endocytosis-linked BAR proteins is the presence of a Src homology 3 (SH3) domain that binds to dynamin and to members of the WASP/Scar family proteins. WASP/Scar proteins form a family of five

N-BAR domain proteins in endocytosis

BAR proteins frequently have an N-terminal amphipathic helix preceding the consensus BAR domain; the combination is referred to as an N-BAR domain 15, 16, 17, 18. Amphipathic helices are often unstructured until they insert into lipid membranes. One side of the amphipathic helix is polar and the other hydrophobic, so that the hydrophobic side can insert into the hydrophobic phase of the lipid bilayer displacing the phospholipids of the membrane. This displacement of the phospholipids on one

F-BAR domain proteins in endocytosis

Evidence for a new class of BAR-related proteins had been accumulating following studies of FER/CIP4 homology (FCH) proteins, which were known to couple actin and endocytic machinery, but were thought to be only loosely associated with BAR proteins. Two landmark studies 14, 36 used a combination of sequence comparisons and structural predictions together with biochemical and cell biological studies to show that FCH proteins were members of an extended BAR family, now termed F-BAR. Sequence

Conclusions and future challenges

It is clear that proteins containing BAR domains function in a wide variety of cellular events to sense highly curved membranes. Here, we have presented current research describing the involvement of BAR domains in endocytic events, in which they clearly have an important role. They act to couple membrane sensing and bending with the recruitment of important endocytic proteins; when dynamin is recruited, this facilitates vesicle fission, and when the Arp2/3 complex is recruited and then

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Phagocytosis is a widespread and evolutionarily conserved process with diverse biological functions, ranging from engulfment of invading microbes during infection to clearance of apoptotic debris in tissue homeostasis. Along with differences in biochemical composition, phagocytic targets greatly differ in physical attributes, such as size, shape, and rigidity, which are now recognized as important regulators of this process. Force exertion at the cell–target interface and cellular mechanical changes during phagocytosis are emerging as crucial factors underlying sensing of such target properties. With technological developments, mechanical aspects of phagocytosis are increasingly accessible experimentally, revealing remarkable organizational complexity of force exertion. An increasingly high-resolution picture is emerging of how target physical cues and cellular mechanical properties jointly govern important steps throughout phagocytic engulfment.

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Trends in Cell Biology

ReviewSpecial issue: Membrane DynamicsBar domain proteins: a role in tubulation, scission and actin assembly in clathrin-mediated endocytosis

Section snippets

The actin cytoskeleton facilitates endocytosis

The actin cytoskeleton is modular

The Arp2/3 complex and the Diaphanous-related formins act as actin filament-generating machines

The actin cytoskeleton deforms and moves membranes

BAR domain proteins are important linkers between membranes and the cytoskeleton

BAR domain proteins in endocytosis

N-BAR domain proteins in endocytosis

F-BAR domain proteins in endocytosis

Conclusions and future challenges

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Review
Special issue: Membrane Dynamics
Bar domain proteins: a role in tubulation, scission and actin assembly in clathrin-mediated endocytosis