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

4 Citations (Scopus)

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 Ca 2+ -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	The EMBO Journal
Volume	42
Issue	23
ISSN	0261-4189
DOIs	https://doi.org/10.15252/embj.2022111122
Publication status	Published - Dec 2023

Keywords

alpha-synuclein
calcium
calmodulin
plasma membrane Ca -ATPase
presynapse

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10.15252/embj.2022111122

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10690453/

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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. The EMBO Journal, 42(23), Article e111122. https://doi.org/10.15252/embj.2022111122

@article{907d6bffd40243f287a5e7246a0dfbd5,

title = "Monomeric α-synuclein activates the plasma membrane calcium pump",

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 Ca 2+ -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. ",

keywords = "alpha-synuclein, calcium, calmodulin, plasma membrane Ca -ATPase, presynapse",

author = "Antoni Kowalski and Cristine Betzer and Larsen, {Sigrid Thirup} and Emil Gregersen and Newcombe, {Estella A} and Bermejo, {Monta{\~n}a Caballero} and Bendtsen, {Viktor Wisniewski} and Jorin Diemer and Ernstsen, {Christina V} and Shweta Jain and Bou, {Alicia Espi{\~n}a} and Langkilde, {Annette Eva} and Nejsum, {Lene N} and Edda Klipp and Robert Edwards and Kragelund, {Birthe B} and Jensen, {Poul Henning} and Poul Nissen",

year = "2023",

month = dec,

doi = "10.15252/embj.2022111122",

language = "English",

volume = "42",

journal = "The EMBO Journal",

issn = "0261-4189",

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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', The EMBO Journal, vol. 42, no. 23, e111122. https://doi.org/10.15252/embj.2022111122

TY - JOUR

T1 - Monomeric α-synuclein activates the plasma membrane calcium pump

AU - Kowalski, Antoni

AU - Betzer, Cristine

AU - Larsen, Sigrid Thirup

AU - Gregersen, Emil

AU - Newcombe, Estella A

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

PY - 2023/12

Y1 - 2023/12

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 Ca 2+ -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 Ca 2+ -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.

KW - alpha-synuclein

KW - calcium

KW - calmodulin

KW - plasma membrane Ca -ATPase

KW - presynapse

UR - http://www.scopus.com/inward/record.url?scp=85175703796&partnerID=8YFLogxK

U2 - 10.15252/embj.2022111122

DO - 10.15252/embj.2022111122

M3 - Journal article

C2 - 37916890

SN - 0261-4189

VL - 42

JO - The EMBO Journal

JF - The EMBO Journal

IS - 23

M1 - e111122

ER -

Monomeric α-synuclein activates the plasma membrane calcium pump

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Keywords

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