CONICET | Buscador de Institutos y Recursos Humanos

Aluminium (Al3+) is involved with the pathophysiology of neurodegenerative disorders, such as Parkinsonism dementia and Alzheimer?s disease. The mechanisms that have been proposed to explain the toxicity of Al3+ are linked to changes in the cellular calcium homeostasis. PMCA is a P-ATPase involved in the regulation of the calcium homeostasis. Its function is to transport Ca2+ from cytoplasm towards the extracellular medium against the electrochemical gradient modulating the cytoplasmic Ca2+ concentration. In previous works, we already showed that Al3+ irreversibly inhibits Ca2+-ATPase activity of PMCA by preventing the dephosphorylation of the pump and that AlCl3 inhibits calcium eﬄux mediated by PMCA in HEK293T cells. The aim of this work was to study if the eﬀect of Al3+ on the protein is aﬀected by the enzyme lipidic environment, since this would provide information of the distinctive eﬀect that Al3+ would have depends on the lipidic composition of the cell membrane where the PMCA is located. To characterize this eﬀect, we reconstituted the enzyme in diﬀerent lipidic environment and evaluated its inhibition by Al3+. In addition, to characterize if the diﬀerences observed were due to an eﬀect of the lipidic environment on the enzyme structure or an Al3+ chelating eﬀect, we measure the interaction of Al3+ with diﬀerent lipidic structures. In the isolated system, increasing concentration of acidic phospholipids decreased the Al3+ eﬀect on PMCA. However, when PMCA is reconstituted with brain extract lipids, Al3+ increased its Ca2+-ATPase activity. These results suggest that Al3+ aﬀects PMCA both by its binding to the enzyme and modifying the biophysical characteristics of the pump lipid environment. Acknowldegments This work was supported by ANCYT PICT 2014 0065, CONICET PIP 0250 and Universidad de Buenos Aires 2014-2017: 20020130100254B