Calcium modulates the domain flexibility and function of an α-actinin similar to the ancestral α-actinin
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Calcium modulates the domain flexibility and function of an α-actinin similar to the ancestral α-actinin. / Pinotsis, Nikos; Zielinska, Karolina; Babuta, Mrigya; Arolas, Joan L; Kostan, Julius; Khan, Muhammad Bashir; Schreiner, Claudia; Salmazo, Anita; Ciccarelli, Luciano; Puchinger, Martin; Gkougkoulia, Eirini A; Ribeiro, Euripedes de Almeida; Marlovits, Thomas C; Bhattacharya, Alok; Djinovic-Carugo, Kristina.
in: P NATL ACAD SCI USA, Jahrgang 117, Nr. 36, 08.09.2020, S. 22101-22112.Publikationen: SCORING: Beitrag in Fachzeitschrift/Zeitung › SCORING: Zeitschriftenaufsatz › Forschung › Begutachtung
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T1 - Calcium modulates the domain flexibility and function of an α-actinin similar to the ancestral α-actinin
AU - Pinotsis, Nikos
AU - Zielinska, Karolina
AU - Babuta, Mrigya
AU - Arolas, Joan L
AU - Kostan, Julius
AU - Khan, Muhammad Bashir
AU - Schreiner, Claudia
AU - Salmazo, Anita
AU - Ciccarelli, Luciano
AU - Puchinger, Martin
AU - Gkougkoulia, Eirini A
AU - Ribeiro, Euripedes de Almeida
AU - Marlovits, Thomas C
AU - Bhattacharya, Alok
AU - Djinovic-Carugo, Kristina
PY - 2020/9/8
Y1 - 2020/9/8
N2 - The actin cytoskeleton, a dynamic network of actin filaments and associated F-actin-binding proteins, is fundamentally important in eukaryotes. α-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 α-actinin-2 (EhActn2) with features expected for the common ancestor of Entamoeba and higher eukaryotic α-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.
AB - The actin cytoskeleton, a dynamic network of actin filaments and associated F-actin-binding proteins, is fundamentally important in eukaryotes. α-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 α-actinin-2 (EhActn2) with features expected for the common ancestor of Entamoeba and higher eukaryotic α-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.
KW - Actinin/chemistry
KW - Calcium/pharmacology
KW - Catalytic Domain
KW - Entamoeba histolytica/genetics
KW - Gene Expression Regulation
KW - Models, Molecular
KW - Protein Conformation
KW - Protein Domains
U2 - 10.1073/pnas.1917269117
DO - 10.1073/pnas.1917269117
M3 - SCORING: Journal article
C2 - 32848067
VL - 117
SP - 22101
EP - 22112
JO - P NATL ACAD SCI USA
JF - P NATL ACAD SCI USA
SN - 0027-8424
IS - 36
ER -