Lateral organization, bilayer asymmetry, and inter-leaflet coupling of biological membranes

Abstract

Understanding of cell membrane organization has evolved significantly from the classic fluid mosaic model. It is now recognized that biological membranes are highly organized structures, with differences in lipid compositions between inner and outer leaflets and in lateral structures within the bilayer plane, known as lipid rafts. These organizing principles are important for protein localization and function as well as cellular signaling. However, the mechanisms and biophysical basis of lipid raft formation, structure, dynamics and function are not clearly understood. One key question, which we focus on in this review, is how lateral organization and leaflet compositional asymmetry are coupled. Detailed information elucidating this question has been sparse because of the small size and transient nature of rafts and the experimental challenges in constructing asymmetric bilayers. Resolving this mystery will require advances in both experimentation and modeling. We discuss here the preparation of model systems along with experimental and computational approaches that have been applied in efforts to address this key question in membrane biology. We seek to place recent and future advances in experimental and computational techniques in context, providing insight into in-plane and transverse organization of biological membranes.

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

“…Contributing factors to domain registration could be transmembrane proteins, lipid interdigitation, membrane curvature, line tension, cholesterol flip-flop, and electrostatic interactions (Nickels et al, 2015) of which chain interdigitation has been invoked as the major contributing factor (May, 2009) but also has been totally dismissed (Collins, 2008). A recent experimental determination of the strength of the coupling parameter that causes domain registration matches a theoretical predictions with values around 0.01 k B T /nm 2 (Putzel et al, 2011; Blosser et al, 2015), but considerably higher values have also been suggested from theoretical considerations (May, 2009).…”

Ions Modulate Stress-Induced Nanotexture in Supported Fluid Lipid Bilayers

“…The first widely accepted membrane model (2), the so-called “fluid mosaic model”, assumes that phospholipids are merely structural molecules in which membrane proteins can move freely. This passive description of the membrane lipids is increasingly challenged by recent findings (3, 4, 5, 6). Studies have shown that the membrane is a highly dynamical structure that actively supports the cell function.…”

“…Studies have shown that the membrane is a highly dynamical structure that actively supports the cell function. Phospholipids play an important role in this new understanding, for example in conferring membrane curvature (7) and actively organizing proteins complexes (6, 8). Despite these advances, our molecular-level understanding of plasma membranes is still limited, partly due to a lack of experimental results.…”

“…Solid-supported membranes are typically immersed in aqueous solution, and only a few nanometers of the solution separate the membrane from the solid support (18). This approach effectively confines the membrane in two dimensions, hence facilitating high-resolution investigations with techniques such as atomic force microscopy (19), fluorescence microscopy (20), fluorescence recovery after photobleaching (FRAP) (21), quartz crystal microbalance (22), and neutron reflectometry (6). Synthetic supported lipid bilayers (23) (SLBs) are routinely used in experimental studies, including for investigating the influence of proteins (24, 25), antibodies (26), functionalized nanoparticles (27), polymers (28), amino acids (29), and antimicrobial peptides (30) on the morphology and biophysical properties of the membrane.…”

The in vivo structure of biological membranes and evidence for lipid domains

“…[13] Through these techniques, a vivid picture of the membrane has emerged. [14–19] Nonetheless, they have significant limitations, and fundamental questions about the ultrastructure of the membrane in vivo remain unresolved. [20]…”