STRUCTURE OF AN ACTIN CROSS LINKING DOMAIN FROM HUMAN FIMBRIN

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Actin crosslinking proteins organize filamentous (F-) actin into higher order assemblies such as bundles and networks which are important for biological processes including cell motility, cytokinesis and tumorigenesis. Fimbrin is a representative member of the largest superfamily of actin crosslinkers which is characterized by a conserved 275 amino acid F-actin binding domain. We have determined the crystal structure of the N-terminal actin binding domain of human fimbrin (ABD1) to 2.4 E resolution, which represents the first high resolution structure of an actin-crosslinking domain. Initial characterization of ABD1 crystals was performed using synchrotron radiation at Brookhaven National Laboratory, Beamline X9B, where the crystals diffracted to at least 1.9 E resolution. ABD1 is an ellipsoid molecule of dimensions (60x40x40E 3, and has a novel fold Hcomposed of two calponin homology (CH) subdomains. CH domains may Hserve to target a number of proteins, including signaling proteins, to Hcytoskeletal components. In collaboration with David DeRosier, we Hhave now docked this x-ray structure into the 28E electron microscopic Hreconstruction of actin filaments decorated with a comparable Hfragmenet of fimbrin. This work has for the first time provided an Hatomic model for the crosslinked assembly.