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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, Vol. 117, No. 36, 08.09.2020, p. 22101-22112.

Research output: SCORING: Contribution to journal › SCORING: Journal article › Research › peer-review

Harvard

Pinotsis, N, Zielinska, K, Babuta, M, Arolas, JL, Kostan, J, Khan, MB, Schreiner, C, Salmazo, A, Ciccarelli, L, Puchinger, M, Gkougkoulia, EA, Ribeiro, EDA, Marlovits, TC, Bhattacharya, A & Djinovic-Carugo, K 2020, 'Calcium modulates the domain flexibility and function of an α-actinin similar to the ancestral α-actinin', P NATL ACAD SCI USA, vol. 117, no. 36, pp. 22101-22112. https://doi.org/10.1073/pnas.1917269117

APA

Pinotsis, N., Zielinska, K., Babuta, M., Arolas, J. L., Kostan, J., Khan, M. B., Schreiner, C., Salmazo, A., Ciccarelli, L., Puchinger, M., Gkougkoulia, E. A., Ribeiro, E. D. A., Marlovits, T. C., Bhattacharya, A., & Djinovic-Carugo, K. (2020). Calcium modulates the domain flexibility and function of an α-actinin similar to the ancestral α-actinin. P NATL ACAD SCI USA, 117(36), 22101-22112. https://doi.org/10.1073/pnas.1917269117

Vancouver

Pinotsis N, Zielinska K, Babuta M, Arolas JL, Kostan J, Khan MB et al. Calcium modulates the domain flexibility and function of an α-actinin similar to the ancestral α-actinin. P NATL ACAD SCI USA. 2020 Sep 8;117(36):22101-22112. https://doi.org/10.1073/pnas.1917269117

Bibtex

@article{41ef79b9bb734d1d8ceebc8b67dae73a,
title = "Calcium modulates the domain flexibility and function of an α-actinin similar to the ancestral α-actinin",
abstract = "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.",
keywords = "Actinin/chemistry, Calcium/pharmacology, Catalytic Domain, Entamoeba histolytica/genetics, Gene Expression Regulation, Models, Molecular, Protein Conformation, Protein Domains",
author = "Nikos Pinotsis and Karolina Zielinska and Mrigya Babuta and Arolas, {Joan L} and Julius Kostan and Khan, {Muhammad Bashir} and Claudia Schreiner and Anita Salmazo and Luciano Ciccarelli and Martin Puchinger and Gkougkoulia, {Eirini A} and Ribeiro, {Euripedes de Almeida} and Marlovits, {Thomas C} and Alok Bhattacharya and Kristina Djinovic-Carugo",
year = "2020",
month = sep,
day = "8",
doi = "10.1073/pnas.1917269117",
language = "English",
volume = "117",
pages = "22101--22112",
journal = "P NATL ACAD SCI USA",
issn = "0027-8424",
publisher = "National Academy of Sciences",
number = "36",

}

RIS

TY - JOUR

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 -