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 af dette arbejde

Publikation: Bidrag til tidsskrift/Konferencebidrag i tidsskrift /Bidrag til avisTidsskriftartikelForskningpeer review

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.

OriginalsprogEngelsk
Artikelnummere111122
TidsskriftThe EMBO Journal
Vol/bind42
Nummer23
ISSN0261-4189
DOI
StatusUdgivet - dec. 2023

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