Calcium modulates the domain flexibility and function of an ?-actinin similar to the ancestral ?-actinin.

ABSTRACT: The actin cytoskeleton, a dynamic network of actin filaments and associated F-actin-binding proteins, is fundamentally important in eukaryotes. ?-Actinins are major F-actin bundlers that are inhibited by Ca²⁺ in nonmuscle cells. Here we report the mechanism of Ca²⁺-mediated regulation of Entamoeba histolytica ?-actinin-2 (EhActn2) with features expected for the common ancestor of Entamoeba and higher eukaryotic ?-actinins. Crystal structures of Ca²⁺-free and Ca²⁺-bound EhActn2 reveal a calmodulin-like domain (CaMD) uniquely inserted within the rod domain. Integrative studies reveal an exceptionally high affinity of the EhActn2 CaMD for Ca²⁺, binding of which can only be regulated in the presence of physiological concentrations of Mg²⁺ Ca²⁺ binding triggers an increase in protein multidomain rigidity, reducing conformational flexibility of F-actin-binding domains via interdomain cross-talk and consequently inhibiting F-actin bundling. In vivo studies uncover that EhActn2 plays an important role in phagocytic cup formation and might constitute a new drug target for amoebic dysentery.

SUBMITTER: Pinotsis N 

PROVIDER: S-EPMC7486759 | biostudies-literature | 2020 Sep

REPOSITORIES: biostudies-literature