title: Structure of the actin-depolymerizing factor homology domain in complex with actin.
abstract: Actin dynamics provide the driving force for many cellular processes including motility and endocytosis. Among the central cytoskeletal regulators are actin-depolymerizing factor (ADF)/cofilin, which depolymerizes actin filaments, and twinfilin, which sequesters actin monomers and caps filament barbed ends. Both interact with actin through an ADF homology (ADF-H) domain, which is also found in several other actin-binding proteins. However, in the absence of an atomic structure for the ADF-H domain in complex with actin, the mechanism by which these proteins interact with actin has remained unknown. Here, we present the crystal structure of twinfilin's C-terminal ADF-H domain in complex with an actin monomer. This domain binds between actin subdomains 1 and 3 through an interface that is conserved among ADF-H domain proteins. Based on this structure, we suggest a mechanism by which ADF/cofilin and twinfilin inhibit nucleotide exchange of actin monomers and present a model for how ADF/cofilin induces filament depolymerization by weakening intrafilament interactions.
authors.affiliation: Program in Cellular Biotechnology, Institute of Biotechnology, University of Helsinki, Helsinki FIN-00014, Finland.
authors.forename: Ville O
authors.initials: VO
authors.lastname: Paavilainen
authors.forename: Esko
authors.initials: E
authors.lastname: Oksanen
authors.forename: Adrian
authors.initials: A
authors.lastname: Goldman
authors.forename: Pekka
authors.initials: P
authors.lastname: Lappalainen
mesh_terms: D008841:Actin Cytoskeleton / Q000737:chemistry; D051339:Actin Depolymerizing Factors / Q000737:chemistry; D000199:Actins / Q000737:chemistry / Q000378:metabolism*; D000255:Adenosine Triphosphate / Q000378:metabolism; D000595:Amino Acid Sequence; D000818:Animals; D017124:Conserved Sequence; D018360:Crystallography, X-Ray; D051345:Destrin / Q000737:chemistry*; D018260:Gelsolin / Q000737:chemistry; D051379:Mice; D008840:Microfilament Proteins / Q000737:chemistry* / Q000378:metabolism*; D008958:Models, Molecular; D008969:Molecular Sequence Data; D011485:Protein Binding; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary; D017386:Sequence Homology, Amino Acid
chemical_list: D051339:Actin Depolymerizing Factors; D000199:Actins; D000255:Adenosine Triphosphate; D051345:Destrin; D018260:Gelsolin; D008840:Microfilament Proteins; C485190:Twf1 protein, mouse