IMDs (green) form filopodia by binding and bending the membrane, and not by bundling the actin (red). Image courtesy of Pekka Lappalainen, University of Helsinki, Finland.
Most actin-dependent processes involve the deformation of cellular membranes. However, the effects of actin-binding proteins on the reshaping of membranes have remained unclear. Mattila et al. investigated the function of the actin-binding proteins missing-in-metastasis (MIM) and insulin receptor substrate p53 (IRSp53) and report, for the first time, that actin-binding proteins can induce protrusions by bending the membrane.
IRSp53 and MIM are large multidomain proteins that contain an IRSp53/MIM domain (IMD) at their N termini. IMDs share structural homology with BAR domains, which bind and deform lipid membranes in vitro and in vivo. But, in contrast to BAR domains, which are involved in the formation of membrane invaginations, IMDs function in the formation of membrane protrusions.
So, do IMDs have a BAR-domain-like membrane-binding activity? Both the long and short IMD isoforms of MIM and the IMD of IRSp53 interacted strongly with phosphatidylinositol-4,5-bisphosphate (PtdIns(4,5)P2)-containing vesicles. IMDs deformed PtdIns(4,5)P2-rich membranes into tubular structures; however, because of a difference in the geometry of the PtdIns(4,5)P2-binding site between the BAR domain and IMDs, IMDs bind to the inner surface of the membrane tubule and therefore promote the formation of plasma-membrane protrusions rather than invaginations.
Mattila et al. also showed that the PtdIns(4,5)P2–IMD interaction is crucial for filopodia formation in mammalian cells. IMD mutants had defects in PtdIns(4,5)P2-binding and lipid-vesicle tubulation activity, and both defects were associated with reduced filopodia formation. By contrast, the previously reported F-actin-bundling or Rac-binding activities of IMD did not contribute to filopodia formation. Filopodia formation was also dependent on IMD binding to actin. Membrane, Rac and actin binding seem to involve roughly the same area of the molecule, indicating that these interactions compete with each other.
In the future, it will be important to investigate the detailed mechanism by which IMD proteins interact with membranes and how these proteins function in cell processes such as migration and morphogenesis.
ORIGINAL RESEARCH PAPER
- Mattila, P. K. et al. Missing-in-metastasis and IRSp53 deform PI(4,5)P2-rich membranes by an inverse BAR domain-like mechanism. J. Cell Biol. 26 March 2007 (doi: doi: 10.1083/jcb.200609176) | Article |
FURTHER READING
- Takenawa, T. & Suetsugu, S. The WASP/WAVE protein network: connecting the membrane to the cytoskeleton. Nature Rev. Mol. Cell Biol. 8, 37–48 (2007) | Article |