Wrapping up a cell biology riddle


New research has revealed how protein filaments drive a key cellular process by physically wrapping around and constricting bits of cell membrane

The process of endocytosis, by which a cell internalizes molecules bound to outward-facing receptors, is essential for a wide variety of cellular functions. During the first steps of endocytosis, the cell membrane invaginates, puckering inward to form a pocket that is ultimately pinched off to become a bubble-like vesicle, which can act as a vehicle for delivering encapsulated molecules to various locations within the cell.

This invagination requires the assembly of various proteins into complexes that associate with the membrane and induce deformation and the subsequent formation of membrane ‘tubules’. Tadaomi Takenawa's group at the Kobe University Graduate School of Medicine has focused much of their work on these proteins, and recently identified a protein domain known as EFC/F-BAR that plays a direct role in membrane tubulation1. At the same time, Shigeyuki Yokoyama's research team at the RIKEN Genomic Sciences Center in Yokohama was studying the Cdc42-interacting protein (CIP4), which happens to contain a functional EFC domain. Yokoyama and Takenawa decided to collaborate on an in-depth structural analysis of EFC in an effort to clarify its function.

They found that EFC domains pair off to form crescent-shaped dimers—much like BAR, another known membrane-binding domain, although the curve is far subtler for EFC domains2. “This explains why the EFC domain generates tubular membranes with diameters that are several times larger than those induced by the BAR domain,” says Yokoyama. Surprisingly, the structural data also suggested that these EFC dimers can further assemble into lengthy filaments, which can tightly wrap around—and thereby extend—tubulations in the cell membrane (Fig. 1). Subsequent microscopic analysis of endocytotic cells would demonstrate that this model was accurate. “The physiological function of the EFC filament was predicted by the structure-function analysis of the EFC domain,” says Yokoyama.

Based on these findings, Yokoyama, Takenawa and colleagues were able to develop a more sophisticated model for endocytosis, where EFC proteins like CIP4 drive early stages of invagination through filament formation, then gradually recruit additional proteins like dynamin, which further constrict the tubules before pinching them off to form mature vesicles.

Yokoyama doesn’t think this is the end of the story, however, and his group is continuing to investigate EFC proteins with Takenawa’s team. “We would like to investigate the function of the full-length protein and its interaction partners,” he says, “because we believe that yet unknown, interesting regulatory mechanisms are hidden in this molecule.”

1. Tsujita, K., Suetsugu, S., Sasaki, N., Furutani, M., Oikawa, T. & Takenawa, T. Coordination between actin cytoskeleton and membrane deformation by a novel membrane tubulation domain of PCH proteins is involved in endocytosis. Journal of Cell Biology 172, 269–279 (2006).

2. Shimada, A., Niwa, H., Tsujita, K., Suetsugu, S., Nitta, K., Hanawa-Suetsugu, K., Akasaka, R., Nishino, Y., Toyama, M., Chen, L. et al. Curved EFC/F-BAR-domain dimers are joined end to end into a filament for membrane invagination in endocytosis. Cell 129, 761–772 (2007).