P-type ATPase are present in nearly all organisms. They maintain electrochemical gradients for many solutes, in particular ions, they control membrane lipid asymmetry, and are crucial components of intricate signaling networks. All P-type ATPases share a common topology with a transmembrane and three cytoplasmic domains and their transport cycle follows a general scheme — the Post-Albers-cycle. Recently, P-type ATPase research has been advanced most significantly by the technological advancements in cryo-EM analysis, which has elucidated many new P-type ATPase structures and mechanisms and revealed several new ways of regulation. In this review, we highlight the progress of the field and focus on special features that are present in the five subfamilies. Hence, we outline the new intersubunit transport model of KdpFABC, the ways in which heavy metal pumps have evolved to accommodate various substrates, the strategies Ca2+ pumps utilize to adapt to different environmental needs, the intricate molecular builds of the ion binding sites in Na,K- and H,K-ATPases, the remarkable hexameric assembly of fungal proton pumps, the many ways in which P4-ATPase lipid flippases are regulated, and finally the deorphanization of P5 pumps. Interestingly many of the described features are found in more than one of the five subfamilies, and mixed and matched together to provide optimal function and precise regulation.

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 here 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 calmodulin, yet independent of the autoinhibitory domain of PMCA, but highly dependent on acidic phospholipids and the membrane-anchoring N-terminus of aSN. On the PMCA molecule, the interaction site is mapped to the acidic lipid-binding site, located within a PMCA-specific linker region connecting the cytosolic A domain and transmembrane segment 3. Our studies point towards a physiological role of monomeric aSN as a stimulator of calcium clearance in neurons through activation of PMCA

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