TY - JOUR T1 - Monomeric α-Synuclein activates the Plasma Membrane Calcium Pump JF - bioRxiv DO - 10.1101/2022.02.21.481193 SP - 2022.02.21.481193 AU - Antoni Kowalski AU - Cristine Betzer AU - Sigrid Thirup Larsen AU - Emil Gregersen AU - Estella Anne Newcombe AU - Montaña Caballero Bermejo AU - Annette Eva Langkilde AU - Birthe Brandt Kragelund AU - Poul Henning Jensen AU - Poul Nissen Y1 - 2022/01/01 UR - http://biorxiv.org/content/early/2022/03/07/2022.02.21.481193.abstract N2 - Alpha-synuclein (aSN) is a membrane-associated and intrinsically disordered protein, well-known for pathological aggregation in neurodegeneration. The physiological function of aSN however 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 that calcium expulsion is activated by aSN and PMCA. From PMCA activity studies we show that soluble, monomeric aSN activates PMCA at par with CaM, yet independent of the autoinhibitory domain of PMCA, but highly dependent on acidic phospholipids and membrane-anchoring of aSN. On PMCA, the key site is mapped to the acidic lipid-binding site, located within a disordered PMCA-specific loop region connecting the cytosolic A domain and transmembrane segment 3. Our studies point towards a novel physiological role of monomeric aSN as a stimulator of calcium clearance in neurons through activation of PMCA.Competing Interest StatementThe authors have declared no competing interest. ER -