Structures of the heart specific SERCA2a Ca                         
                        2+
                                                 -ATPase

Aljona Sitsel; Joren De Raeymaecker; Nikolaj Düring Drachmann; Rita Derua; Susanne Smaardijk; Jacob Lauwring Andersen; Ilse Vandecaetsbeek; Jialin Chen; Marc De Maeyer; Etienne Waelkens; Claus Olesen; Peter Vangheluwe; Poul Nissen

doi:10.15252/embj.2018100020

Structures of the heart specific SERCA2a Ca ²⁺ -ATPase

Aljona Sitsel
, Joren De Raeymaecker
, Nikolaj Düring Drachmann
, Rita Derua
, Susanne Smaardijk
, Jacob Lauwring Andersen
, Ilse Vandecaetsbeek
, Jialin Chen
, Marc De Maeyer
, Etienne Waelkens
, Claus Olesen^*
, Peter Vangheluwe
, Poul Nissen

^*Corresponding author for this work

Research output: Contribution to journal/Conference contribution in journal/Contribution to newspaper › Journal article › Research › peer-review

47 Citations (Scopus)

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 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.

Original language	English
Article number	e100020
Journal	EMBO Journal
Volume	38
Issue	5
ISSN	0261-4189
DOIs	https://doi.org/10.15252/embj.2018100020
Publication status	Published - Mar 2019

Keywords

Ca transport
Ca -ATPase
crystal structure
heart failure
molecular dynamics

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10.15252/embj.2018100020

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6396164/pdf/EMBJ-38-e100020.pdf

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Sitsel, A., De Raeymaecker, J., Drachmann, N. D., Derua, R., Smaardijk, S., Andersen, J. L., 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), Article e100020. https://doi.org/10.15252/embj.2018100020

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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 = mar,

doi = "10.15252/embj.2018100020",

language = "English",

volume = "38",

journal = "EMBO Journal",

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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

Structures of the heart specific SERCA2a Ca ²⁺ -ATPase. / Sitsel, Aljona; De Raeymaecker, Joren; Drachmann, Nikolaj Düring et al.
In: EMBO Journal, Vol. 38, No. 5, e100020, 03.2019.

Research output: Contribution to journal/Conference contribution in journal/Contribution to newspaper › Journal article › Research › peer-review

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 - https://www.scopus.com/pages/publications/85061920789

U2 - 10.15252/embj.2018100020

DO - 10.15252/embj.2018100020

M3 - Journal article

C2 - 30777856

AN - SCOPUS:85061920789

SN - 0261-4189

VL - 38

JO - EMBO Journal

JF - EMBO Journal

IS - 5

M1 - e100020

ER -