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 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 towards a novel physiological role of monomeric aSN as a stimulator of calcium clearance in neurons through activation of PMCA

SUBMITTER: Antoni Kowalski 

PROVIDER: S-SCDT-10_15252-EMBJ_2022111122 | biostudies-other |

REPOSITORIES: biostudies-other