Bni1p Formin Homology 2 (FH2) Domain complexed with ATP-actin
Saccharomyces cerevisiae (Baker's yeast)
The cytoskeleton of eukaryotic cells is constructed by three kinds of filaments : actin filaments, intermediate filaments and microtubules. The actin filaments , positioned mainly beneath the plasma membrane, are responsible for preserving cellular shape. They play an important role in the processes of cell division, migration, polarity, membrane protrusion, muscular contraction etc. Actin filaments are formed by helical polymerization of actin monomers. This is a very slow process and other proteins are employed to assist and speed up the nucleation and elongation of the filament. The Arp2/3 complex binds at the sides of existing filaments and nucleates branches, while formins induce filament nucleation or attach themselves to the barbed ends of the fibrils and boost further elongation.
The structure of an actin monomer (from rabbit) bound to the highly conserved FH2 domain of the yeast formin Bni1p is presented here. Wrapping of FH2 around actin is achieved by the binding of two helical subdomains named post and knob that are connected by a central three-helix bundle. A very interesting structure extends from the knob. Due to its shape it is called 'lasso'. The 'lasso' connects the knob of one FH2 domain to the post subdomain of the next, a bridge that spans about 42 angstroms. The functional unit of FH2 is a dimer that forms a ring. This ring encompasses three actin monomers : the uppermost actin(1) is bound to the knob of FH2(1); the middle actin(2) is bound to both the post of FH2(1) and the knob of FH2(2); and finally the lowermost actin(3) is bound to the post of FH2(2). Now, if we imagine that this dimer structure is at the barbed end of a long filament we can easily see an explanation about the process of assisted elongation. When all four binding sites of the formin dimer are bound to three actin monomers as explained above, filament extension is blocked. The recruitment of new monomers can be achieved via the following mechanism. The uppermost actin(1) is being released from the FH2 dimer clamps, i.e. the filament 'moves' up. Or one may say that the dimer ring 'slides down'. In this new conformation the middle actin(2) is now bound only to the knob of FH2(1) (before it was the post of FH2(1)), while the lower actin(3) is bound to both the post of FH2(1) and the knob of FH2(2). In that way the post of FH2(2) is now the free binding site, where another actin(4) monomer can bind. The same process repeats again and again. It has to be noted that FH2 does not work as a mere dimer. It forms an extended helix of interconnected monomers that resembles a spring, through which the actin filament passes. This spiral gives a much more stable framework for fibril support.
Protein Data Bank (PDB)
Otomo, T. Tomchick, D.R. Otomo, C. Panchal, S.C. Machius, M. Rosen, M.K.; "Structural basis of actin filament nucleation and processive capping by a formin homology 2 domain"; Nature; (2005) 433:488-494 PubMed:15635372.
author: Rossen Apostolov