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Interactions stabilizing the C-terminal helix of human phospholipid scramblase 1 in lipid bilayers: A computational
Tom Venken1, Anne-Sophie Schillinger2, Edvin Fuglebakk2
1Department of Molecular Biology, University of Bergen, Pb. 7803, N-5020 Bergen, Norway; Computational Biology Unit, Department of Informatics, University of Bergen, Pb. 7803, N-5020, Norway; Flemish Institute for Technological Research, VITO, Mol B-2400, Belgium.
Abstract:
The human phospholipid scramblase 1 (SCR) distributes lipids non-selectively between the cellular membrane leaflets. SCR has long been thought to be mostly localized in the cytoplasm (amino acids 1-287) and anchored to the membrane via the insertion of a 19 amino acid long transmembrane C-terminal helix (CTH, 288-306), which further extends to the exoplasmic side with a 12 amino acid long tail (307-318). Little is known about the structure of this protein, but recent experimental data on two CTH peptides (288-306 and 288-318) show that they insert through phospholipid bilayers and that the presence of cholesterol improves their affinity for lipid vesicles. Yet the sequence of the CTH (288KMKAVMIGACFLIDFMFFE306) contains an aspartic acid (D301), which is not exactly a prototypical amino acid for single-pass transmembrane helices. In this study, we investigate how the polar aspartate residue is accommodated in lipid bilayers containing POPC with and without cholesterol, using all-atom molecular dynamics simulations. We identify two cholesterol-binding sites: (i) A291, F298 and L299 and (ii) L299, F302 and E306 and suggest that cholesterol plays a role in stabilizing the helix in a transmembrane position. We suggest that the presence of the aspartate could be functionally relevant for the scramblase protein activity.