Regulation of phospholipid distribution in the lipid bilayer by flippases and scramblases

Abstract

Cellular membranes function as permeability barriers that separate cells from the external environment or partition cells into distinct compartments. These membranes are lipid bilayers composed o f g ly ce ro ph os ph olipids, sphingolipids and cholesterol, in which proteins are embedded. G l y ce r o ph o s ph olipids and sphingolipids freely move laterally, whereas t r a ns v e rse m o v em ent between lipid bilayers is limited. Phospholipids are asymmetrically distributed between membrane leaflets but change their location in biological processes, serving as signalling molecules or enzyme activators. Designated proteins -flippases and scramblases -mediate this lipid movement between the bilayers. Flippases mediate the confined localization of specific phospholipids (phosphatidylserine (PtdSer) and phosphatidylethanolamine) to the cytoplasmic leaflet. Scramblases randomly scramble phospholipids between leaflets and facilitate the exposure of PtdSer on the cell surface, which serves as an important signalling molecule and as an 'eat me' signal for phagocytes. Defects in flippases and scramblases cause various human diseases. We herein review the recent research on the structure of flippases and scramblases and their physiological roles. Although still poorly understood, we address the mechanisms by which they translocate phospholipids between lipid bilayers and how defects cause human diseases. SectionsThe role of P4-type ATPases in lipid 'flipping' between the bilayer. P-type ATPases constitute a large protein family that transport cations and lipids across the membrane 24 . They are named 'P-type' because a conserved aspartic acid is transiently modified by phosphorylation during the reaction cycle. A phylogenic analysis divided the family into five subfamilies (P1-P5 types). Similar to other P-type ATPases, P4-ATPases are membrane proteins with cytoplasmic amino c Caspase-mediated PtdSer exposure Apoptotic bodies

Lipid scrambling is a general feature of protein insertases

“…Overall, lipid scramblases have been elusive players in membrane homeostasis, and their identities are only recently starting to emerge (Sakuragi and Nagata, 2023). Our study more than doubles the number of known lipid scramblases, describing tens of new ones.…”

“…While the role of scramblases in membrane biogenesis and homeostasis is widely accepted (Holthuis et al, 2022; Sakuragi and Nagata, 2023), their identity is mostly unknown, and only a handful of scramblases have been identified and characterized. These include mainly plasma membrane proteins, such as the well-studied TMEM16 (Brunner et al, 2014; Suzuki et al, 2013, 2010) and XK families, that scramble phosphatidylserine during apoptosis (Sakuragi and Nagata, 2023).…”

“…While the role of scramblases in membrane biogenesis and homeostasis is widely accepted (Holthuis et al, 2022; Sakuragi and Nagata, 2023), their identity is mostly unknown, and only a handful of scramblases have been identified and characterized. These include mainly plasma membrane proteins, such as the well-studied TMEM16 (Brunner et al, 2014; Suzuki et al, 2013, 2010) and XK families, that scramble phosphatidylserine during apoptosis (Sakuragi and Nagata, 2023). Lipid scramblases of intracellular organelles have been more elusive (Sakuragi and Nagata, 2023), but recently discovered ER scramblases, VMP1 and TMEM41B, are proposed to work in combination with lipid transport proteins to facilitate lipid transport from the ER (Ghanbarpour et al, 2021; Huang et al, 2021; Li et al, 2021).…”

Phagocytic clearance of dying cells and its implications

“…When phagocytes such as macrophages, dendritic cells, or healthy neighbors are in close proximity to the dying cell, specific molecules on the apoptotic cells are recognized by specific receptors on the engulfing cell leading to subsequent intracellular signaling, cytoskeletal reorganization, and corpse internalization 13 . While there are many ligands exposed on cells undergoing apoptosis, the best detailed is the exposure of the phospholipid phosphatidylserine (PtdSer) 14,15 . PtdSer is normally kept via an active and energy dependent process on the inner leaflet but gets exposed on the outer leaflet as part of the apoptotic process 15,16 .…”

“…While there are many ligands exposed on cells undergoing apoptosis, the best detailed is the exposure of the phospholipid phosphatidylserine (PtdSer) 14,15 . PtdSer is normally kept via an active and energy dependent process on the inner leaflet but gets exposed on the outer leaflet as part of the apoptotic process 15,16 . This PtdSer in turn, gets recognized by multiple PtdSer recognition receptors—either directly, or indirectly, via intermediary bridging molecules 16,17 .…”