Monomeric α-synuclein activates the plasma membrane calcium pump

Antoni Kowalski; Cristine Betzer; Sigrid Thirup Larsen; Emil Gregersen; Estella A. Newcombe; Montaña Caballero Bermejo; Viktor Wisniewski Bendtsen; Jorin Diemer; Christina V. Ernstsen; Shweta Jain; Alicia Espiña Bou; Annette Eva Langkilde; Lene N. Nejsum; Edda Klipp; Robert Edwards; Birthe B. Kragelund; Poul Henning Jensen; Poul Nissen

doi:10.15252/embj.2022111122

Monomeric α-synuclein activates the plasma membrane calcium pump

Antoni Kowalski^*, Cristine Betzer, Sigrid Thirup Larsen, Emil Gregersen, Estella A. Newcombe, Montaña Caballero Bermejo, Viktor Wisniewski Bendtsen, Jorin Diemer, Christina V. Ernstsen, Shweta Jain, Alicia Espiña Bou, Annette Eva Langkilde, Lene N. Nejsum, Edda Klipp, Robert Edwards, Birthe B. Kragelund, Poul Henning Jensen, Poul Nissen

^*Corresponding author for this work

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

3 Citations (Scopus)

15 Downloads (Pure)

Abstract

Alpha-synuclein (aSN) is a membrane-associated and intrinsically disordered protein, well known for pathological aggregation in neurodegeneration. However, the physiological function of aSN is disputed. Pull-down experiments have pointed to plasma membrane Ca²⁺-ATPase (PMCA) as a potential interaction partner. From proximity ligation assays, we find that aSN and PMCA colocalize at neuronal synapses, and we show that calcium expulsion is activated by aSN and PMCA. We further show that soluble, monomeric aSN activates PMCA at par with calmodulin, but independent of the autoinhibitory domain of PMCA, and highly dependent on acidic phospholipids and membrane-anchoring properties of aSN. On PMCA, the key site is mapped to the acidic lipid-binding site, located within a disordered PMCA-specific loop connecting the cytosolic A domain and transmembrane segment 3. Our studies point toward a novel physiological role of monomeric aSN as a stimulator of calcium clearance in neurons through activation of PMCA.

Original language	English
Article number	e111122
Journal	EMBO Journal
Volume	42
Issue number	23
Number of pages	21
ISSN	0261-4189
DOIs	https://doi.org/10.15252/embj.2022111122
Publication status	Published - 2023

Bibliographical note

Publisher Copyright:
© 2023 The Authors. Published under the terms of the CC BY 4.0 license.

Keywords

alpha-synuclein
calcium
calmodulin
plasma membrane Ca-ATPase
presynapse

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10.15252/embj.2022111122Licence: CC BY

FulltextFinal published version, 3.13 MBLicence: CC BY

Cite this

Kowalski, A., Betzer, C., Larsen, S. T., Gregersen, E., Newcombe, E. A., Bermejo, M. C., Bendtsen, V. W., Diemer, J., Ernstsen, C. V., Jain, S., Bou, A. E., Langkilde, A. E., Nejsum, L. N., Klipp, E., Edwards, R., Kragelund, B. B., Jensen, P. H., & Nissen, P. (2023). Monomeric α-synuclein activates the plasma membrane calcium pump. EMBO Journal, 42(23), [e111122]. https://doi.org/10.15252/embj.2022111122

Monomeric α-synuclein activates the plasma membrane calcium pump. / Kowalski, Antoni; Betzer, Cristine; Larsen, Sigrid Thirup; Gregersen, Emil; Newcombe, Estella A.; Bermejo, Montaña Caballero; Bendtsen, Viktor Wisniewski; Diemer, Jorin; Ernstsen, Christina V.; Jain, Shweta; Bou, Alicia Espiña; Langkilde, Annette Eva; Nejsum, Lene N.; Klipp, Edda; Edwards, Robert; Kragelund, Birthe B.; Jensen, Poul Henning; Nissen, Poul.

In: EMBO Journal, Vol. 42, No. 23, e111122, 2023.

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

Kowalski, A, Betzer, C, Larsen, ST, Gregersen, E, Newcombe, EA, Bermejo, MC, Bendtsen, VW, Diemer, J, Ernstsen, CV, Jain, S, Bou, AE, Langkilde, AE, Nejsum, LN, Klipp, E, Edwards, R, Kragelund, BB, Jensen, PH & Nissen, P 2023, 'Monomeric α-synuclein activates the plasma membrane calcium pump', EMBO Journal, vol. 42, no. 23, e111122. https://doi.org/10.15252/embj.2022111122

Kowalski, Antoni ; Betzer, Cristine ; Larsen, Sigrid Thirup ; Gregersen, Emil ; Newcombe, Estella A. ; Bermejo, Montaña Caballero ; Bendtsen, Viktor Wisniewski ; Diemer, Jorin ; Ernstsen, Christina V. ; Jain, Shweta ; Bou, Alicia Espiña ; Langkilde, Annette Eva ; Nejsum, Lene N. ; Klipp, Edda ; Edwards, Robert ; Kragelund, Birthe B. ; Jensen, Poul Henning ; Nissen, Poul. / Monomeric α-synuclein activates the plasma membrane calcium pump. In: EMBO Journal. 2023 ; Vol. 42, No. 23.

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abstract = "Alpha-synuclein (aSN) is a membrane-associated and intrinsically disordered protein, well known for pathological aggregation in neurodegeneration. However, the physiological function of aSN is disputed. Pull-down experiments have pointed to plasma membrane Ca2+-ATPase (PMCA) as a potential interaction partner. From proximity ligation assays, we find that aSN and PMCA colocalize at neuronal synapses, and we show that calcium expulsion is activated by aSN and PMCA. We further show that soluble, monomeric aSN activates PMCA at par with calmodulin, but independent of the autoinhibitory domain of PMCA, and highly dependent on acidic phospholipids and membrane-anchoring properties of aSN. On PMCA, the key site is mapped to the acidic lipid-binding site, located within a disordered PMCA-specific loop connecting the cytosolic A domain and transmembrane segment 3. Our studies point toward a novel physiological role of monomeric aSN as a stimulator of calcium clearance in neurons through activation of PMCA.",

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AU - Bermejo, Montaña Caballero

AU - Bendtsen, Viktor Wisniewski

AU - Diemer, Jorin

AU - Ernstsen, Christina V.

AU - Jain, Shweta

AU - Bou, Alicia Espiña

AU - Langkilde, Annette Eva

AU - Nejsum, Lene N.

AU - Klipp, Edda

AU - Edwards, Robert

AU - Kragelund, Birthe B.

AU - Jensen, Poul Henning

AU - Nissen, Poul

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N2 - Alpha-synuclein (aSN) is a membrane-associated and intrinsically disordered protein, well known for pathological aggregation in neurodegeneration. However, the physiological function of aSN is disputed. Pull-down experiments have pointed to plasma membrane Ca2+-ATPase (PMCA) as a potential interaction partner. From proximity ligation assays, we find that aSN and PMCA colocalize at neuronal synapses, and we show that calcium expulsion is activated by aSN and PMCA. We further show that soluble, monomeric aSN activates PMCA at par with calmodulin, but independent of the autoinhibitory domain of PMCA, and highly dependent on acidic phospholipids and membrane-anchoring properties of aSN. On PMCA, the key site is mapped to the acidic lipid-binding site, located within a disordered PMCA-specific loop connecting the cytosolic A domain and transmembrane segment 3. Our studies point toward a novel physiological role of monomeric aSN as a stimulator of calcium clearance in neurons through activation of PMCA.

AB - Alpha-synuclein (aSN) is a membrane-associated and intrinsically disordered protein, well known for pathological aggregation in neurodegeneration. However, the physiological function of aSN is disputed. Pull-down experiments have pointed to plasma membrane Ca2+-ATPase (PMCA) as a potential interaction partner. From proximity ligation assays, we find that aSN and PMCA colocalize at neuronal synapses, and we show that calcium expulsion is activated by aSN and PMCA. We further show that soluble, monomeric aSN activates PMCA at par with calmodulin, but independent of the autoinhibitory domain of PMCA, and highly dependent on acidic phospholipids and membrane-anchoring properties of aSN. On PMCA, the key site is mapped to the acidic lipid-binding site, located within a disordered PMCA-specific loop connecting the cytosolic A domain and transmembrane segment 3. Our studies point toward a novel physiological role of monomeric aSN as a stimulator of calcium clearance in neurons through activation of PMCA.

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