Molecular mechanism for inhibition of twinfilin by phosphoinositides
| Autor: | Maria Kalimeri, Markku Hakala, Ilpo Vattulainen, Pekka Lappalainen, Giray Enkavi |
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| Přispěvatelé: | Institute of Biotechnology, Department of Physics, Pekka Lappalainen / Principal Investigator |
| Jazyk: | angličtina |
| Rok vydání: | 2018 |
| Předmět: |
0301 basic medicine
PHOSPHATIDYLINOSITOL 4 5-BISPHOSPHATE BUDDING YEAST CAPPING PROTEIN Protein domain Amino Acid Motifs macromolecular substances Molecular Dynamics Simulation Phosphatidylinositols Biochemistry Protein–protein interaction 03 medical and health sciences chemistry.chemical_compound Mice 0302 clinical medicine FACTOR HOMOLOGY DOMAIN Protein Domains MEMBRANE DYNAMICS Animals CELL REGULATION Protein–lipid interaction Binding site Cytoskeleton MEDIATED ENDOCYTOSIS Molecular Biology Actin ACTIN-FILAMENT Microfilament Proteins Cell Biology Actin cytoskeleton 030104 developmental biology Phosphatidylinositol 4 5-bisphosphate chemistry Models Chemical PLASMA-MEMBRANE Biophysics FORCE-FIELD 1182 Biochemistry cell and molecular biology 030217 neurology & neurosurgery |
| Zdroj: | Hakala, M, Kalimeri, M, Enkavi, G, Vattulainen, I & Lappalainen, P 2018, ' Molecular mechanism for inhibition of twinfilin by phosphoinositides ', Journal of Biological Chemistry, vol. 293, no. 13, pp. 4818-4829 . https://doi.org/10.1074/jbc.RA117.000484 |
| Popis: | Membrane phosphoinositides control organization and dynamics of the actin cytoskeleton by regulating the activities of several key actin-binding proteins. Twinfilin is an evolutionarily conserved protein that contributes to cytoskeletal dynamics by interacting with actin monomers, filaments, and the heterodimeric capping protein. Twinfilin also binds phosphoinositides, which inhibit its interactions with actin, but the underlying mechanism has remained unknown. Here, we show that the high-affinity binding site of twinfilin for phosphoinositides is located at the C-terminal tail region, whereas the two actin-depolymerizing factor (ADF)/cofilin-like ADF homology domains of twinfilin bind phosphoinositides only with low affinity. Mutagenesis and biochemical experiments combined with atomistic molecular dynamics simulations reveal that the C-terminal tail of twinfilin interacts with membranes through a multivalent electrostatic interaction with a preference toward phosphatidylinositol 3,5-bisphosphate (PI(3,5)P2), PI(4,5)P2, and PI(3,4,5)P3. This initial interaction places the actin-binding ADF homology domains of twinfilin in close proximity to the membrane and subsequently promotes their association with the membrane, thus leading to inhibition of the actin interactions. In support of this model, a twinfilin mutant lacking the C-terminal tail inhibits actin filament assembly in a phosphoinositide-insensitive manner. Our mutagenesis data also reveal that the phosphoinositide- and capping protein- binding sites overlap in the C-terminal tail of twinfilin, suggesting that phosphoinositide binding additionally inhibits the interactions of twinfilin with the heterodimeric capping protein. The results demonstrate that the conserved C-terminal tail of twinfilin is a multifunctional binding motif, which is crucial for interaction with the heterodimeric capping protein and for tethering twinfilin to phosphoinositide-rich membranes. |
| Databáze: | OpenAIRE |
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