Abstract
Phosphatidylserine flippase (P4-ATPase) transports PS from the outer to the inner leaflet of the lipid bilayer in the membrane to maintain PS asymmetry, which is important for biological activities of the cell. ATP11A is expressed in multiple tissues and plays a role in myotube formation. However, the detailed cellular function of ATP11A remains elusive. Mutation analysis revealed that I91, L308, and E897 residues in ATP8A2 are important for flippase activity. In order to investigate the roles of these corresponding amino acid residues in ATP11A protein, we assessed the expression and cellular localization of the respective ATP11A mutant proteins. ATP11A mainly localizes to the Golgi and plasma membrane when coexpressed with the β-subunit of the complex TMEM30A. Y300F mutation causes reduced ATP11A expression, and Y300F and D913K mutations affect correct localization of the Golgi and plasma membrane. In addition, Y300F and D913K mutations also affect PS flippase activity. Our data provides insight into important residues of ATP11A.
Highlights
Phospholipids of eukaryotic cell membranes are asymmetrically distributed, with phosphatidylserine (PS) and phosphatidylethanolamine (PE) concentrated mainly in the cytoplasmic leaflet of the membrane bilayer, while phosphatidylcholine (PC) and sphingolipids mainly positioned only on the exoplasmic leaflet [1,2,3,4,5,6]
ATP8A1, ATP8A2, ATP8B1, ATP8B2, ATP8B4, ATP10A, ATP10D, ATP11A, and ATP11C are localized to the plasma membrane, whereas ATP9A, ATP9B, ATP10B, and ATP11B are localized to intracellular membranes [1, 4, 7, 15, 19, 20]
By investigating the expression pattern and flippase activity of these mutated ATP11A proteins, we demonstrated that variants of Y300F and D913K affected correct Golgi localization and the amount of PS internalization in the plasma membrane
Summary
Phospholipids of eukaryotic cell membranes are asymmetrically distributed, with phosphatidylserine (PS) and phosphatidylethanolamine (PE) concentrated mainly in the cytoplasmic leaflet of the membrane bilayer, while phosphatidylcholine (PC) and sphingolipids mainly positioned only on the exoplasmic leaflet [1,2,3,4,5,6]. Mounting evidence reveals that the asymmetrically distributed phospholipids are maintained by P4-ATPases ( called flippases), which translocate phospholipids from the exoplasmic leaflet to the cytoplasmic leaflet [1, 3,4,5,6, 17]. Among the cell surface-localized P4-ATPases, ATP8A1, ATP8A2, ATP8B1, ATP11A, and ATP11C have been shown to catalyze the inward translocation of PS at the plasma membrane [4, 7, 15, 19, 20]. TMEM30A interacts with the vast majority of P4ATPases, including ATP11A, and is critical for its proper functions [21]
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