Transbilayer phospholipid movement facilitates annexin 2 translocation across membranes

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Ashkenazi, Avraham 
Williamson, Athena 

Annexins are cytosolic phospholipid binding proteins that can be found on the outer leaflet of the plasma membrane. Extracellular annexin functions include fibrinolysis activity and cell migration, among other functions. Despite having well described extracellular functions, the mechanism of annexin transport from the cytoplasmic inner leaflet to the extracellular outer leaflet of the plasma membrane remains unclear. Here, we show that the transbilayer movement of phospholipids facilitates the transport of annexins A2 and A5 across membranes in cells and in liposomes. We identified TMEM16F (anoctamin-6) as a lipid scramblase required for transport of these annexins to the outer leaflet of the plasma membrane. This work reveals a mechanism for annexin translocation across membranes which depends on plasma membrane phospholipid remodelling.

Annexin, Lipid flipping, Protein translocation, TMEM16F, Annexin A2, Annexin A5, Anoctamins, Cell Membrane, HeLa Cells, Humans, Lipid Bilayers, Liposomes, Phospholipid Transfer Proteins, Phospholipids, Protein Transport
Journal Title
Journal of Cell Science
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The Company of Biologists Ltd.
Wellcome Trust (095317/Z/11/Z)
Wellcome Trust (100574/Z/12/Z)
Medical Research Council (MC_UU_12012/1)
Biotechnology and Biological Sciences Research Council (BB/P010911/1)
Medical Research Council (MC_UU_12012/5)
MRC (MC_UU_00014/5)
This work was supported by Wellcome Trust Strategic Award [100574/Z/12/Z], MRC Metabolic Diseases Unit [MRC_MC_UU_12012/5], BBSRC Future Leader Fellowship (BB/P010911/1) and the Isaac Newton Trust/Wellcome Trust ISSF/University of Cambridge joint research grant for SES and KM, Wellcome Trust (Principal Research Fellowship to DCR (095317/Z/11/Z)), Strategic Grant to Cambridge Institute for Medical Research (100140/Z/12/Z), UK Dementia Research Institute (funded by the MRC, Alzheimer’s Research UK and the Alzheimer’s Society) (DCR), and by the Federation of European Biochemical Societies (FEBS Long-Term Fellowship) for AA.