Interleaflet Coupling, Pinning, and Leaflet Asymmetry—Major Players in Plasma Membrane Nanodomain Formation

Abstract

The plasma membrane has a highly asymmetric distribution of lipids and contains dynamic nanodomains many of which are liquid entities surrounded by a second, slightly different, liquid environment. Contributing to the dynamics is a continuous repartitioning of components between the two types of liquids and transient links between lipids and proteins, both to extracellular matrix and cytoplasmic components, that temporarily pin membrane constituents. This make plasma membrane nanodomains exceptionally challenging to study and much of what is known about membrane domains has been deduced from studies on model membranes at equilibrium. However, living cells are by definition not at equilibrium and lipids are distributed asymmetrically with inositol phospholipids, phosphatidylethanolamines and phosphatidylserines confined mostly to the inner leaflet and glyco- and sphingolipids to the outer leaflet. Moreover, each phospholipid group encompasses a wealth of species with different acyl chain combinations whose lateral distribution is heterogeneous. It is becoming increasingly clear that asymmetry and pinning play important roles in plasma membrane nanodomain formation and coupling between the two lipid monolayers. How asymmetry, pinning, and interdigitation contribute to the plasma membrane organization is only beginning to be unraveled and here we discuss their roles and interdependence.

Lipid Structure and Composition Control Consequences of Interleaflet Coupling in Asymmetric Vesicles

“…They proposed that both coupling and a lack of coupling are possible, depending on lipid composition (16,(19)(20)(21)(45)(46)(47)(48). The induction of ordered domains in one leaflet arising from ordered domains in the opposite leaflet has been reported in some lipid compositions (15,16,(19)(20)(21)45), whereas in other cases, loosening or destruction of ordered domains by when a disordered state is present in the opposite leaflet has been reported (47,49). However, it must be pointed out that studies using light microscopy fail to detect domain formation if only nanosized domains form or if the partition properties of the fluorescent probe chosen are insufficient to detect when domains form in some lipid compositions.…”

“…Interactions between the two leaflets can be crucial for domain formation (15). In the case of strong leaflet coupling, the properties of one leaflet are impacted by the other leaflet such that inner and outer leaflets have very similar physical properties/domain formation.…”

Analysing plasma membrane asymmetry of lipid organisation by fluorescence lifetime and correlation spectroscopy

“…The transient assemblies exhibit unique lifespans governed by the mutual interactions of their components. In addition to the lateral heterogeneity, a fundamental feature of the plasma membrane is the asymmetry of lipid composition between the two leaflets [4][5][6] . The dynamic lateral heterogeneity of the membrane is essential for cell signalling 7 while the asymmetric arrangement of lipids across the plasma membrane is found to be critical in the regulation of several biological processes, including apoptosis 8 , cell-cell fusion 9 and signalling in immune cells 10 .…”

“…SM, ceramide, GSLs) and cholesterol 11 . In the plasma membrane, PC and sphingolipids are prevalent in the outer leaflet while aminophospholipids such as PS, and PE are prevalent in the inner leaflet 4 . Since the outer-leaflet comprises more domain forming lipids and the inner-leaflet is in direct contact with the cytoskeleton, it is expected that the organization and dynamics of the two leaflets are different.…”

Osh Proteins Control Nanoscale Lipid Organization Necessary for PI(4,5)P ₂ Synthesis

“…Biological membranes are not homogeneous, and lipids are not uniformly distributed within a membrane. Differences in the physical properties of lipids are proposed to induce membrane lipid segregation and the formation of lipid nanodomains (Fujimoto and Parmryd, 2017;Lingwood and Simons, 2010). Accordingly, although lipid composition per se is not fully conserved across organisms, the biophysical principles that govern membrane organization are universally applied (Kaiser et al, 2011;van Meer et al, 2008).…”