Crystal structure ofAnophelesgambiae actin depolymerizing factor explains high affinity to monomeric actin

Abstract

AbstractActin is an intrinsically dynamic protein, the function and state of which are modulated by actin-binding proteins. Actin depolymerizing factors (ADF)/cofilins are ubiquitous actin-binding proteins that accelerate actin turnover. Malaria is an infectious disease caused by parasites of the genusPlasmodium, which belong to the phylum Apicomplexa. The parasites require two hosts to complete their life cycle: the definitive host, or the vector, which is anAnophelesspp. mosquito, and a vertebrate intermediate host, such as humans. Here, the crystal structure of the malaria vectorAnopheles gambiaeADF (AgADF) is reported.AgADF has a conserved ADF/cofilin fold with six central β-strands surrounded by five α-helices with a long β-hairpin loop protruding out of the structure. The G and F-actin binding sites ofAgADF are conserved, and the structure shows features of potential importance for regulation by membrane binding and redox state.AgADF binds monomeric ATP- and ADP-actin with a high affinity, having a nanomolar Kd, and binds to and effectively destabilizes actin filaments.