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

Citation:

Pinotsis N, Zielinska K, Babuta M, Arolas JL, Kostan J, Khan MB, Schreiner C, Salmazo A, Ciccarelli L, Puchinger M, et al. Calcium modulates the domain flexibility and function of an alpha-actinin similar to the ancestral alpha-actinin. Proc Natl Acad Sci U S A. 2020;117:22101-22112.

Abstract:

The actin cytoskeleton, a dynamic network of actin filaments and associated F-actin-binding proteins, is fundamentally important in eukaryotes. alpha-Actinins are major F-actin bundlers that are inhibited by Ca(2+) in nonmuscle cells. Here we report the mechanism of Ca(2+)-mediated regulation of Entamoeba histolytica alpha-actinin-2 (EhActn2) with features expected for the common ancestor of Entamoeba and higher eukaryotic alpha-actinins. Crystal structures of Ca(2+)-free and Ca(2+)-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 Ca(2+), binding of which can only be regulated in the presence of physiological concentrations of Mg(2+) Ca(2+) 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.

Notes:

Pinotsis, NikosZielinska, KarolinaBabuta, MrigyaArolas, Joan LKostan, JuliusKhan, Muhammad BashirSchreiner, ClaudiaSalmazo, AnitaCiccarelli, LucianoPuchinger, MartinGkougkoulia, Eirini ARibeiro, Euripedes de Almeida JrMarlovits, Thomas CBhattacharya, AlokDjinovic-Carugo, KristinaengWT_/Wellcome Trust/United Kingdom201543/Z/16/Z/WT_/Wellcome Trust/United KingdomResearch Support, Non-U.S. Gov'tProc Natl Acad Sci U S A. 2020 Sep 8;117(36):22101-22112. doi: 10.1073/pnas.1917269117. Epub 2020 Aug 26.

Contact Details

Biochemistry, Chemistry Department
National and Kapodistrian University of Athens
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Nikos Pinotsis

Associate Professor, Chemistry