Monomeric α-synuclein activates the plasma membrane calcium pump

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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.
OriginalsprogEngelsk
Artikelnummere111122
TidsskriftEMBO Journal
Vol/bind42
Udgave nummer23
Antal sider21
ISSN0261-4189
DOI
StatusUdgivet - 2023

Bibliografisk note

Funding Information:
This work was supported by a “Mobility plus, 3 edition” fellowship grant of the Polish Ministry of Science and Higher Education to AK, a postdoctoral research grant from the Extremadura Province (PO17009) to MCB, by a PhD stipend from the Aarhus Graduate School of Science at Aarhus University to STL, by a collaborative grant from H. Lundbeck A/S to PHJ, by Lundbeck Foundation grants R223‐2015‐4222 for PHJ and R248‐2016‐2518 for Danish Research Institute of Translational Neuroscience‐DANDRITE, Nordic‐EMBL Partnership for Molecular to PN and PHJ, and by funds from a project 2 research grant from the Independent Research Fund Denmark (7014‐00328B) and the Brainstruc research center (R155‐2015‐2666) and a professorship grant (R310‐2018‐3713) of the Lundbeck Foundation to PN. Further support was given by the European Union's Horizon 2020 research and innovation program under the Marie Sklodowska‐Curie grant agreement No. 101023654, awarded to EAN. and the Novo Nordisk Foundation (#NNF18OC0033926 to BBK). All NMR data were recorded at cOpenNMR, an infrastructure facility funded by the Novo Nordisk Foundation (#NNF18OC0032996). The mathematical modeling work was funded by the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) under Germany's Excellence Strategy—The Berlin Mathematics Research Center MATH+ (EXC‐2046/1, project ID: 390685689) to EK. rd

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

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