Structures of the heart specific SERCA2a Ca 2+ -ATPase

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Structures of the heart specific SERCA2a Ca 2+ -ATPase. / Sitsel, Aljona; De Raeymaecker, Joren; Drachmann, Nikolaj Düring; Derua, Rita; Smaardijk, Susanne; Andersen, Jacob Lauwring; Vandecaetsbeek, Ilse; Chen, Jialin; De Maeyer, Marc; Waelkens, Etienne; Olesen, Claus; Vangheluwe, Peter; Nissen, Poul.

In: EMBO Journal, Vol. 38, No. 5, e100020, 03.2019.

Research output: Contribution to journal/Conference contribution in journal/Contribution to newspaperJournal articleResearchpeer-review

Harvard

Sitsel, A, De Raeymaecker, J, Drachmann, ND, Derua, R, Smaardijk, S, Andersen, JL, Vandecaetsbeek, I, Chen, J, De Maeyer, M, Waelkens, E, Olesen, C, Vangheluwe, P & Nissen, P 2019, 'Structures of the heart specific SERCA2a Ca 2+ -ATPase', EMBO Journal, vol. 38, no. 5, e100020. https://doi.org/10.15252/embj.2018100020

APA

Sitsel, A., De Raeymaecker, J., Drachmann, N. D., Derua, R., Smaardijk, S., Andersen, J. L., ... Nissen, P. (2019). Structures of the heart specific SERCA2a Ca 2+ -ATPase. EMBO Journal, 38(5), [e100020]. https://doi.org/10.15252/embj.2018100020

CBE

Sitsel A, De Raeymaecker J, Drachmann ND, Derua R, Smaardijk S, Andersen JL, Vandecaetsbeek I, Chen J, De Maeyer M, Waelkens E, Olesen C, Vangheluwe P, Nissen P. 2019. Structures of the heart specific SERCA2a Ca 2+ -ATPase. EMBO Journal. 38(5). https://doi.org/10.15252/embj.2018100020

MLA

Vancouver

Sitsel A, De Raeymaecker J, Drachmann ND, Derua R, Smaardijk S, Andersen JL et al. Structures of the heart specific SERCA2a Ca 2+ -ATPase. EMBO Journal. 2019 Mar;38(5). e100020. https://doi.org/10.15252/embj.2018100020

Author

Sitsel, Aljona ; De Raeymaecker, Joren ; Drachmann, Nikolaj Düring ; Derua, Rita ; Smaardijk, Susanne ; Andersen, Jacob Lauwring ; Vandecaetsbeek, Ilse ; Chen, Jialin ; De Maeyer, Marc ; Waelkens, Etienne ; Olesen, Claus ; Vangheluwe, Peter ; Nissen, Poul. / Structures of the heart specific SERCA2a Ca 2+ -ATPase. In: EMBO Journal. 2019 ; Vol. 38, No. 5.

Bibtex

@article{d93b95aed03c499ab6e96b7ac8014e44,
title = "Structures of the heart specific SERCA2a Ca 2+ -ATPase",
abstract = "The sarcoplasmic/endoplasmic reticulum Ca 2+ -ATPase 2a (SERCA2a) performs active reuptake of cytoplasmic Ca 2+ and is a major regulator of cardiac muscle contractility. Dysfunction or dysregulation of SERCA2a is associated with heart failure, while restoring its function is considered as a therapeutic strategy to restore cardiac performance. However, its structure has not yet been determined. Based on native, active protein purified from pig ventricular muscle, we present the first crystal structures of SERCA2a, determined in the CPA-stabilized E2 -ALF - 4 form (3.3 {\AA}) and the Ca 2+ -occluded [Ca 2 ]E1-AMPPCP form (4.0 {\AA}). The structures are similar to the skeletal muscle isoform SERCA1a pointing to a conserved mechanism. We seek to explain the kinetic differences between SERCA1a and SERCA2a. We find that several isoform-specific residues are acceptor sites for post-translational modifications. In addition, molecular dynamics simulations predict that isoform-specific residues support distinct intramolecular interactions in SERCA2a and SERCA1a. Our experimental observations further indicate that isoform-specific intramolecular interactions are functionally relevant, and may explain the kinetic differences between SERCA2a and SERCA1a.",
keywords = "Ca transport, Ca -ATPase, crystal structure, heart failure, molecular dynamics",
author = "Aljona Sitsel and {De Raeymaecker}, Joren and Drachmann, {Nikolaj D{\"u}ring} and Rita Derua and Susanne Smaardijk and Andersen, {Jacob Lauwring} and Ilse Vandecaetsbeek and Jialin Chen and {De Maeyer}, Marc and Etienne Waelkens and Claus Olesen and Peter Vangheluwe and Poul Nissen",
year = "2019",
month = "3",
doi = "10.15252/embj.2018100020",
language = "English",
volume = "38",
journal = "E M B O Journal",
issn = "0261-4189",
publisher = "Wiley-Blackwell Publishing Ltd",
number = "5",

}

RIS

TY - JOUR

T1 - Structures of the heart specific SERCA2a Ca 2+ -ATPase

AU - Sitsel, Aljona

AU - De Raeymaecker, Joren

AU - Drachmann, Nikolaj Düring

AU - Derua, Rita

AU - Smaardijk, Susanne

AU - Andersen, Jacob Lauwring

AU - Vandecaetsbeek, Ilse

AU - Chen, Jialin

AU - De Maeyer, Marc

AU - Waelkens, Etienne

AU - Olesen, Claus

AU - Vangheluwe, Peter

AU - Nissen, Poul

PY - 2019/3

Y1 - 2019/3

N2 - The sarcoplasmic/endoplasmic reticulum Ca 2+ -ATPase 2a (SERCA2a) performs active reuptake of cytoplasmic Ca 2+ and is a major regulator of cardiac muscle contractility. Dysfunction or dysregulation of SERCA2a is associated with heart failure, while restoring its function is considered as a therapeutic strategy to restore cardiac performance. However, its structure has not yet been determined. Based on native, active protein purified from pig ventricular muscle, we present the first crystal structures of SERCA2a, determined in the CPA-stabilized E2 -ALF - 4 form (3.3 Å) and the Ca 2+ -occluded [Ca 2 ]E1-AMPPCP form (4.0 Å). The structures are similar to the skeletal muscle isoform SERCA1a pointing to a conserved mechanism. We seek to explain the kinetic differences between SERCA1a and SERCA2a. We find that several isoform-specific residues are acceptor sites for post-translational modifications. In addition, molecular dynamics simulations predict that isoform-specific residues support distinct intramolecular interactions in SERCA2a and SERCA1a. Our experimental observations further indicate that isoform-specific intramolecular interactions are functionally relevant, and may explain the kinetic differences between SERCA2a and SERCA1a.

AB - The sarcoplasmic/endoplasmic reticulum Ca 2+ -ATPase 2a (SERCA2a) performs active reuptake of cytoplasmic Ca 2+ and is a major regulator of cardiac muscle contractility. Dysfunction or dysregulation of SERCA2a is associated with heart failure, while restoring its function is considered as a therapeutic strategy to restore cardiac performance. However, its structure has not yet been determined. Based on native, active protein purified from pig ventricular muscle, we present the first crystal structures of SERCA2a, determined in the CPA-stabilized E2 -ALF - 4 form (3.3 Å) and the Ca 2+ -occluded [Ca 2 ]E1-AMPPCP form (4.0 Å). The structures are similar to the skeletal muscle isoform SERCA1a pointing to a conserved mechanism. We seek to explain the kinetic differences between SERCA1a and SERCA2a. We find that several isoform-specific residues are acceptor sites for post-translational modifications. In addition, molecular dynamics simulations predict that isoform-specific residues support distinct intramolecular interactions in SERCA2a and SERCA1a. Our experimental observations further indicate that isoform-specific intramolecular interactions are functionally relevant, and may explain the kinetic differences between SERCA2a and SERCA1a.

KW - Ca transport

KW - Ca -ATPase

KW - crystal structure

KW - heart failure

KW - molecular dynamics

UR - http://www.scopus.com/inward/record.url?scp=85061920789&partnerID=8YFLogxK

U2 - 10.15252/embj.2018100020

DO - 10.15252/embj.2018100020

M3 - Journal article

VL - 38

JO - E M B O Journal

JF - E M B O Journal

SN - 0261-4189

IS - 5

M1 - e100020

ER -