BAR Proteins: Architects of Cellular Membranes

In a living cell, structures are constantly built and remodeled, a process that relies on the precise shaping of cellular membranes. These flexible barriers are sculpted into complex forms like tubes, vesicles, and protrusions. The molecular architects responsible for this work are BAR domain proteins, a family of proteins that directly bind to and bend membranes. This shaping gives them the forms needed to carry out the cell’s functions, ensuring the internal landscape is both organized and responsive.

The Architectural Structure of BAR Proteins

The name BAR originates from the first proteins in which this functional region was identified: Bin, Amphiphysin, and Rvs. The core of a BAR protein’s function lies in its unique three-dimensional shape. The functional unit is a dimer, where two identical BAR protein molecules pair up. This partnership forms an elongated, crescent-shaped structure. Each protein monomer is composed of three long alpha-helices that bundle together with its partner, creating a stable six-helix structure.

This intrinsic curve is a fundamental feature of the BAR domain. The concave, or inner, face of the crescent-shaped dimer is positively charged. This allows it to be electrostatically attracted to the negatively charged head groups of the lipids that make up the cell membrane. The specific dimensions of this curve predetermine the degree of bending it will impose on a membrane it associates with.

Shaping the Cell: The Function of Membrane Curvature

The primary role of BAR proteins is to generate and stabilize curved membranes. They achieve this through a few key mechanisms that leverage their unique structure. The most direct method is scaffolding, where the intrinsic banana shape of the BAR domain dimer acts as a rigid mold. When multiple BAR protein dimers are recruited to a specific area of the membrane, they self-assemble into larger arrays, and their collective crescent shape physically forces the lipid bilayer to bend and adopt a similar curvature. This process is driven by the electrostatic attraction between the positively charged concave face of the protein and the negatively charged membrane surface.

A second mechanism employed by some BAR proteins involves wedge insertion. Certain family members possess additional structures, such as an N-terminal amphipathic helix, which can insert itself into one leaflet of the lipid bilayer. This helix acts like a wedge, pushing the lipid molecules apart and creating a local imbalance that initiates or enhances membrane bending. This mechanism can work in concert with scaffolding to generate the high degree of curvature needed for forming vesicles and tubules.

During endocytosis, BAR proteins like endophilin and amphiphysin are recruited to the plasma membrane to help pinch off vesicles, bringing nutrients and signaling molecules into the cell. The reverse process, exocytosis, which releases hormones and neurotransmitters, also relies on membrane curvature to fuse vesicles with the cell surface. Furthermore, cell migration, a process involving the extension of finger-like protrusions called filopodia, depends on BAR proteins to shape the membrane at the leading edge of a moving cell.

A Family of Shapers: Types of BAR Domains

The classical BAR domains, such as those found in amphiphysin, possess a pronounced crescent shape that is ideal for generating the highly curved, narrow tubules seen in processes like endocytosis. Their structure fits snugly onto membranes with a small radius of curvature, either inducing this shape or stabilizing it once formed.

A major subfamily is the F-BAR (Fes/Cip4 Homology) domain. F-BAR domains are structurally similar to classical BARs but have a much shallower curve. This makes them suited for generating or associating with membrane structures that have a larger diameter, such as wider tubules or gentle invaginations at the cell surface. Proteins containing F-BAR domains, like CIP4, are often involved in the early stages of membrane deformation and can link membrane remodeling to the underlying actin cytoskeleton.

In contrast to the concave shapes of classical and F-BAR domains, the I-BAR (Inverse BAR) domain proteins have a convex, or outwardly curved, shape. Instead of promoting invaginations that bud into the cell’s cytoplasm, I-BAR proteins stabilize protrusions that push outward from the cell surface. They bind to the inner membrane of these protrusions, such as filopodia, using their convex surface to support negative membrane curvature. Proteins like IRSp53 use their I-BAR domains to facilitate these extensions, which are important for cell motility and environmental sensing.

When the Architects Fail: BAR Proteins in Disease

When BAR proteins malfunction, the structural integrity and dynamic processes of the cell can break down, leading to a variety of human diseases. Because membrane shaping is so fundamental, errors in this process have far-reaching consequences.

In cancer, the ability of malignant cells to change shape is directly related to their capacity to invade surrounding tissues and metastasize to distant sites. This process requires extensive membrane remodeling. F-BAR proteins like CIP4 and FBP17 have been implicated in the formation of invadopodia, actin-rich protrusions that cancer cells use to degrade the extracellular matrix and invade tissues. Dysregulation of these proteins can therefore contribute to the aggressive behavior of tumors, such as in breast and bladder cancer. Another BAR protein, Bin1, can act as a tumor suppressor, and its loss is correlated with the progression of lung and liver carcinomas.

Neurological disorders are also frequently linked to faulty BAR protein function. The communication between nerve cells depends on the efficient release and uptake of neurotransmitters via synaptic vesicles, a process heavily reliant on endocytosis. Defects in BAR proteins like amphiphysin and endophilin can impair this vesicle recycling, disrupting neuronal signaling. Such defects have been implicated in conditions like Alzheimer’s disease, where the dynamin-binding protein (DNMBP) is involved, and even Huntington’s disease, through the interaction of huntingtin with CIP4. Mutations in amphiphysin 2 are known to cause a form of centronuclear myopathy, a disease affecting muscle cells that rely on intricate membrane tubules for contraction.