Lipid somersaults: Uncovering the mechanisms of protein-mediated lipid flipping

Abstract

Membrane lipids diffuse rapidly in the plane of the membrane but their ability to flip spontaneously across a membrane bilayer is hampered by a significant energy barrier. Thus spontaneous flip-flop of polar lipids across membranes is very slow, even though it must occur rapidly to support diverse aspects of cellular life. Here we discuss the mechanisms by which rapid flip-flop occurs, and what role lipid flipping plays in membrane homeostasis and cell growth. We focus on conceptual aspects, highlighting mechanistic insights from biochemical and in silico experiments, and the recent, ground-breaking identification of a number of lipid scramblases.

Lipids and Ions Traverse the Membrane by the Same Physical Pathway in the nhTMEM16 Scramblase

“…The mechanism by which scramblases catalyze rapid exchange of lipids between the two leaflets of a bilayer has been a long-sought question (Bevers and Williamson, 2016;Pomorski and Menon, 2016). Unlike ion channels that transport small, spherical hydrophilic substrates, scramblases must provide a conduction mechanism that accommodates both hydrophilic head groups and extended hydrophobic tails of phospholipids at the same time.…”

“…Because it is energetically costly to move the polar head group through the hydrophobic core of the membrane, scramblases must segregate the polar and non-polar regions of the amphipathic phospholipid during transport. Even before a lipid scramblase was identified, various mechanisms were proposed for the transbilayer movement of lipids (Bevers and Williamson, 2016;Pomorski and Menon, 2016). One model proposed that transmembrane proteins alter lipid packing in a way that enhances the chance for a lipid to transverse the membrane (Kol et al, 2003;Kol et al, 2004).…”

“…Dissipation of this asymmetry in response to the elevation of cytoplasmic Ca 2+ concentration is a ubiquitous signaling mechanism critical for diverse cellular events including blood coagulation, bone mineralization, and cell-cell interaction (Fadok et al, 1992;Fadok et al, 2001;Sahu et al, 2007;Bratton and Henson, 2008;Sanyal and Menon, 2009;Bevers and Williamson, 2016;Nagata et al, 2016;Pomorski and Menon, 2016). Phospholipid scrambling is mediated by phospholipid scramblases, which harvest the energy of the phospholipid gradient to drive the nonspecific and bidirectional transport of phospholipids between leaflets.…”

Elimination of the unnecessary: Intra- and extracellular signaling by anionic phospholipids

“…Two possible mechanisms for this re-shuffling of PS are proposed. The activation of a calcium dependent scramblase can rapidly catalyze the inversion of phospholipids that are asymmetrically located on the plasma membrane [54]. The rate of scramblase activity (>10,000 phospholipids per second) far exceeds the ATP dependent flippase activity of (~1–100 ATP per second).…”

“…The rate of scramblase activity (>10,000 phospholipids per second) far exceeds the ATP dependent flippase activity of (~1–100 ATP per second). Inactivation of the flippase concomitant with scramblase activation, has been proposed as the most efficient way to achieve PS exposure on the outer membrane leaflet [54, 55]. Experimentally, this concept was demonstrated by nitrosative stress under non-apoptotic conditions, wherein selective inhibition of the aminophospholipid translocase (flippase) resulted in PS externalization and recognition of these non-apoptotic cells by macrophages [56] – a phenomenon referred to as “buried alive” [57].…”