Structure of the Amino Terminal Actin Binding Domain of Human Fimbrin

Sharon C. Goldsmith, Navin Pokala⁺, Alexander A. Fedorov, Paul Matsudaira* and Steven C. Almo

Department of Biochemistry, Albert Einstein College of Medicine, Bronx, New York 10461 USA, and *Whitehead Institute for Biomedical Research and Department of Biology, Massachussetts Institute of Technology, Cambridge, Massachusetts 20142 USA. ⁺Present address: Department of Molecular and Cell Biology, University of California, Berkeley, California 94720 USA.

Actin crosslinking proteins direct the assembly of specific filamentous actin (F-actin) structures which are involved in cell motility, cytokinesis, the regulation of cell morphology and sarcomere formation. Fimbrin is a ubiquitous eukaryotic protein that belongs to the largest family of crosslinking proteins, which is characterized by a conserved 275 amino acid F-actin binding domain. Fimbrin contains two tandem repeats of the actin binding domain which direct the formation of tight parallel actin bundles observed in microvilli and stereocilia. This family includes -actinin, spectrin, ABP-120 and dystrophin, the protein defective in Duchenne Muscular Dystrophy. Amino acid sequence analysis demonstrates weak homology within each half of the individual F-actin binding domains. Genetic and biochemical studies have identified potential actin binding sites in several family members. As a first step towards defining an atomic model of the interaction between this family of crosslinking proteins and actin, we report the 2.4 Å structure of the first actin binding domain (ABD1) of human fimbrin. The structure reveals a novel fold composed of two structurally homologous subdomains and allows for the mapping of regions implicated in F-actin binding.

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